ES2598503T3 - New 7-deazapurine nucleoside cytostatics - Google Patents

Abstract

A compound of the formula I: ** Formula ** Where: R1 is a (C1-C6) alkyl, a hydroxy (C1-C6) alkyl, an aryl, an aryl (C1-C6) alkyl, a heteroaryl selected from furanyl , thienyl, pyrrolyl, thiazoyl, imidazolyl, pyridyl, selenophenyl, or pyrazolyl, or heteroaryl (C1-C6) alkyl, wherein each aryl or heteroaryl is optionally substituted with one or more groups selected from (C1-C6) alkyl, (C1- C6) alkoxy, (C1-C6) alkylthio, halo, amino, nitro, cyano, trifluoromethyl, or hydroxy; and R2 is a hydrogen, a heteroaryl, a halo or an aryl that is optionally substituted with one or more groups selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, halo, amino, nitro, cyano, trifluoromethyl, or hydroxy; or one of its salts; As long as every time R1 is an unsubstituted phenyl, then R2 is not hydrogen.

Description

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New cytostatic nucleosides 7-deazapurine Description

Background of the invention

[0001] Currently, there is a need for new agents that are useful for treating cancer.

Summary of the invention

[0002] Some nucleoside derivatives that are potentially useful in the treatment of cancer were presented in WO2005 / 021568 A2, WO00 / 75158 A2 or by Hocek M. et al (J.Med. Chem. 2005.48 (18), 58695873 ), Silhar P. et al (Org. Lett. 2004,16 (19) 3225-3228 and Bioorg. Med. Chem. 2008, 16 2328-2366). Ramasamy K. et al. (J. Med. Chem. 1990903, 1220-1225) presents the synthesis of nucleoside derivatives of 7- deazapurine as potential anti-cancer compounds.

[0003] This invention facilitates anti cancer compounds. Also, in an implementation of the invention a compound of the invention is presented, which is a compound of the formula I:

R1 is (C1-C6) alkyl, hydroxy (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl, heteroaryl selected from furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyridyl, selenophenyl or pyrazolyl, or heteroaryl (C1 -C6) alkyl, where each aryl or heteroaryl is optionally substituted with one or more groups selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, halo, amino, nitro, cyano, trifluoromethyl , or hydroxy; and R2 is hydrogen, heteroaryl, halo, or aryl which are optionally substituted with one or more groups selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, halo, amino, nitro, cyano , trifluoromethyl, or hydroxy; or one of its salts.

[0004] The invention also presents a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one of its pharmaceutically acceptable excipients.

[0005] The invention also presents compounds of the formula I, or a pharmaceutically acceptable salt thereof, for use in a method for inhibiting tumor growth or proliferation of tumor / cancerous cells in vitro or in vivo which comprises contacting a subject, who needs that treatment, with a compound of the formula I, or a pharmaceutically acceptable salt thereof.

[0006] The invention also presents a compound of the formula I, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer, in an animal, which comprises administering to said animal a compound of the formula I, or one of its pharmaceutically acceptable salts.

[0007] The invention also presents compounds of the formula I, or a pharmaceutically acceptable salt thereof, for use in a method for the inhibition of a neoplasic disease in an animal comprising, administering to said animal a compound of the formula I, or one of its pharmaceutically acceptable salts.

[0008] The invention also presents the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, to prepare a medicament for inhibiting the growth of tumor / cancer cells or cell proliferation in tumor / cancer cells, or for delay the progress of the cell cycle in tumor / cancer cells, and for the treatment of cancer in an animal.

image 1

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OH OH

(I)

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[0009] The invention also presents the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, to prepare a medicament for inhibiting a neoplasic disease in an animal.

[0010] The invention also presents synthetic processes and synthetic intermediates that are useful for preparing the compounds of the formula (I) or their salts.

Detailed description

[0011] For the purpose of interpreting this specification, the following definitions shall apply and whenever appropriate, the terms used in the singular shall also include the plural and vice versa.

[0012] As used herein, the term "alkyl" refers to a branched or unbranched hydrocarbon particle. Preferably the alkyl comprises 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, / so-propyl, n-butyl, sec-butyl, / so-butyl, ferc-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. When an alkyl group includes one or more unsaturated bonds, they may be referred to as alkenyl (double bond) or alkynyl (triple bond) groups. In addition, when an alkyl group is linked to an aryl group (defined below), it may be referred to as an "arylalkyl" group.

[0013] As used herein, the term "alkoxy" refers to an alkyl-O-, where the alkyl is defined in earlier sections of this document. Representative examples of alkoxis include, but are not limited to, methoxis, ethoxis, propoxis, 2-propoxis, butoxis, ferc-butoxis, pentyloxies, hexyloxies, cyclopropyloxy-, cyclohexyloxy- and the like. As used herein, the term "lower alkoxy" refers to alkoxy groups having 1-7 carbons and preferably 1-4 carbons.

[0014] The term "aryl" refers to groups of aromatic monodyl or two-chain aromatic hydrocarbons having 620 carbon atoms in the ring portion. Preferably, the aryl is a (C6-C1o) aryl. Non-limiting examples include phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of which may be optionally substituted by

I-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halos, hydroxy, alkoxy, acyl, C-alkyl (O) -O--, aryl-O--, heteroaryl-O-- optionally substituted, aminos, thiols, alkylthio, arylthios, nitros, cyano, carboxis, alkyl-OC (O) -, carbamoyls, alkylthio, sulfonyls, sulfonamides, optionally substituted heterocycloalkyl and the like.

[0015] In addition, the term "aryl" as used herein, also refers to an aromatic substituent that can be an individual aromatic ring, or several aromatic rings that fuse together, covalently bind, or bind to a common group such as a methylene or ethylene molecule. The common linker group may also be a carbonyl such as benzophenone or oxygen such as diphenylether or nitrogen such as diphenylamine.

[0016] As used herein, the term "heteroaryl" refers to an annular system.

monodyl- or bidcyclic- or polydicyclic-fused, having 5-14 members, having 1 to 8 heteroatoms selected from N, O, S or Se. Preferably, the heteroaryl is a 5-10 membered ring system. Commonly, heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-

imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4 -, or 5-

isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2, 3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3-or 4-pyridazinyl, 3- , 4-, or

5- pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl.

[0017] The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloalkyl rings, where the radical or the point of adhesion is in the heteroaromatic ring. Non-limiting examples include, but are not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-3-4-5-6-, o7-isoindolyl, 2- , 3-4-5-6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, o8-purinyl, 1-2-, 3-, 4-, 6-7-8-, o9-quinolizinyl, 2-3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1- , 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-5-6-7-, o8-phthalazinyl, 2-3-4-5-, o6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-,

7- o8-cinolinyl, 2-, 4-6-o7-pteridinyl, 1-2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3 -, 4-, 5-, 6-, 7-, or 8-

carbzaolyl, 1-3-4-, 5-, 6-, 7-, 8-o9-carbolinyl, 1-2-3-, 4- 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-,

8- o9-acridinyl, 1-, 2-, 4-5-6-7-8-o9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10- phenatrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, o9-phenazinyl, 1-2-, 3-, 4-, 6-, 7-8-9-o10-phenothiazinyl , 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-,

6- o1-, 3-, 4-5-6-7-8-, 9-, o10-benzisoqinolinyl, 2-, 3-, 4-, or thieno [2,3-b] furanyl, 2-, 3 -, 5-, 6-, 7-, 8-, 9-, 10 -, or

II- 7H-pyrazino [2,3-c] carbazolyl, 2-, 3-, 5-, 6-, or 7-2H- furo [3,2-b] -pyranyl, 2-, 3-, 4- , 5-, 7-, or 8-5H-pyrido [2,3-d] -o-oxazinyl, 1-, 3-, o5-1H-pyrazolo [4,3-d] -oxazolyl, 2-, 4 -, or 54H-imidazo [4,5-d] thiazolyl, 3-, 5-, or 8-pyrazino [2,3- d] pyridazinyl, 2-, 3-, 5-, o6-imidazo [2,1 -b] thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo [3,4-c] cinolinyl, 1-, 2-, 3-, 4-, 5-, 6- , 8-,

9-, 10, o11-4H-pyrido [2,3-c] carbazolyl, 2-, 3-, 6-, or 7-imidazo [1,2-b] [1,2,4] triazinyl, 7- benzo [b] thienyl, 2-, 4-, 5-, 6-,

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or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4- , 5-, 6-, 7-, 8-, or

9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, o8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo [1,2- b] [2] benzazapinyl. Typical fused heteroari groups include but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- , or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-,

3-, 4-, 5-, 6-, or 7-benzo [b] thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-,

o7-benzothiazolyl.

[0018] A heteroaryl group could be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bidcyclic.

[0019] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0020] As used herein, the term "isomers" refers to different compounds that have the same molecular formula. In addition, as used herein, the term "an optical isomer" refers to any of several stereoisomeric configurations that may exist for a specific compound of this invention and includes geometric isomers. It is understood that a substituent could adhere to the chiral center or to a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. The "enantiomers" are a pair of stereo isomers that are not mirror images and cannot be superimposed between sl A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. The term used to designate a racemic mixture when appropriate. The term "diastereomer" refers to a stereoisomer that has at least 2 asymmetric atoms, but which are not mirror images between sn The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry in each chiral carbon could be specified either by R or S. Resolved compounds whose absolute configuration is unknown may be designated as (+) or (-), depending on the direction (dextro- or levogyro) in which they rotate the polarized light in the plane at the wavelength of the sodium line D. Some of the compounds described herein contain one or more asymmetric centers and may, therefore, give rise to enantiomers, diastereomers, and other stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R) - or (S). The intention of this invention is to include all possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. (R) - and (S) - optically active isomers can be prepared using tuning or chiral reagents, or using conventional techniques. If the compound contains a double bond, the substituent could be an E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans- configuration. All tautomeric forms must also be included.

[0021] As used herein, the term "pharmaceutically acceptable salts" refers to

salts that retain the effectiveness and biological properties of the compounds of this invention and, which are not undesirable from the biological point of view or from any other point of view. In many cases, the compounds of this invention are capable of forming acids and / or base salts due to the presence of amino and / or carboxyl groups or groups similar to these (for example, phenol or hydroxamic acid). Pharmaceutically acceptable acid addition salts may be formed with inorganic acids or organic acids. Inorganic acids from which they can be derived from salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, metric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, acid

glycolic, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, acid

smoking, tartaric acid, dtrico acid, benzoic acid, cinnamic acid, madnelic acid, acid

methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salidic acid, and the like. You go out

Pharmaceutically acceptable additions from bases can be formed with inorganic and organic bases. The inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, already similar; Particularly preferred is ammonium, potassium, sodium, calcium and magnesium salts. The organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines that include naturally occurring substituted amines, cyclic amines, basic ionic exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, latripropylamine, and ethanolamine, the pharmaceutically acceptable salts of this invention can be synthesized from a parent compound, from a basic or acidic particle, or by conventional chemical methods. Generally, those salts can be prepared by reacting to free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg, or K), or by reacting to forms of free bases of these compounds with a stoichiometric amount of the appropriate acid. Those fractions are commonly run in water or in an organic solvent, or in a mixture of the 2. Generally, an aqueous medium such as ether, such as ethyl acetate, such as ethanol, as isopropanol, or as acetonitrile, is preferred. When this is practical. Lists of additional suitable salts can be found in, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), which is incorporated herein by reference.

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[0022] As used herein, the term "pharmaceutically acceptable carrier / excipient" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, anti bacterial agents, fungicidal agents) , isotonic agents, agents that delay absorption, salts, preservatives, medications, drug stabilizers, linkers, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, colorants, such as their materials and combinations, as you know it Any person with knowledge in the industry (refer to, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference). The use of any conventional carrier in the therapeutic or pharmaceutical compositions is contemplated, except if it is incompatible with the active ingredient.

[0023] The term "therapeutically effective amount" of a compound of this invention refers to an amount of the compound of this invention that will cause the biological or medical response of a subject, or relieve the symptoms, delay or slow the progression of the disease. , or avoid a disease, etc. In a preferred implementation, the "effective amount" refers to the amount that inhibits or reduces the proliferation of cancerous cells, or that inhibits or reduces tumor growth / cancer in vitro or in vivo, or inhibits or reduces neoplasic disease in a subject such as a mairnfero. In another preferred implementation, it also refers to the amount that reduces the size of the primary tumor / cancer, inhibits the infiltration of the cancerous cells to the peripheral organs, delays or stops the tumor metastasis, or alleviates, at least to some extent, one or more symptoms associated with the tumor or cancer, etc.

[0024] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mai ^ ero. A subject also refers to, for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In a preferred implementation, the subject is a human.

[0025] As used herein, the term "a disease" or "a disorder" refers to any functional disturbance or abnormality; a morbid physical or mental state. Refer to Dorland's Illustrated Medical Dictionary, (W.B. Saunders Co. 27th ed. 1988).

[0026] As used herein, the term "inhibition" or "inhibit" refers to the reduction or suppression of a specific condition, symptom or disease, or a significant reduction in the base line of the activity of an activity. or biological process. In one implementation, it refers to the ability to cause the reduction of a tumor or the growth of cancer, or the reduction in the size of the tumor or cancer.

[0027] As used herein, the term "treat" or "treatment" of any disease or disorder refers, in an implementation, to alleviating the disease or disorder (ie, counteracting or reducing the development of disease or at least one of its chemical symptoms). In another implementation the term "treat" or "treatment" refers to alleviating at least one physical parameter, which may not be discernible by the patient. In another additional implementation, the term "treat" or "treatment" refers to the modulation of the disease or disorder, either physically (for example, the stabilization of an unusable symptom), psychologically (for example, the stabilization of a physical parameter), or both. In another additional implementation, the term "treat" or "treatment" refers to preventing or delaying the onset or development or progress of the disease or disorder.

[0028] As used herein, the term "un", "one", "el" and similar terms used in the context of this invention (especially in the context of the claims) should be considered to encompass the singular and plural unless otherwise indicated in this document or clearly contradicted by the context. The recitation of the ranges of values in this document has the sole purpose of serving as a summary method to refer individually to each separate value that falls within that range. Unless otherwise indicated in this document, each individual value is incorporated into the specification as if it were recited individually in this document. All methods described herein may be performed in any suitable order unless otherwise indicated in this document or when otherwise indicated by the context. The use of any and all examples, or the example language (for example, "as is") indicated herein has the sole purpose of better illustrating the invention and not of establishing a limitation on the focus of the invention. No language in the specification should be considered as indicating any undeclared element essential for the use of the invention.

[0029] In one aspect, this invention provides a compound of the formula (I): where:

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image3

Ri is (Ci-C6) alkyl, hydroxy (Ci-C6) alkyl, aryl, aryl (Ci-C6) alkyl, heteroaryl, heteroaryl (Ci-C6) alkyl, or halo, where each aryl or heteroaryl is optionally substituted with one or more groups selected from (C-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, halo, amino, nitro, cyano, trifluoromethyl, or hydroxy; Y

R2 is hydrogen, heteroaryl, halo or aryl which may be optionally substituted with one or more groups selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, halo, amino, nitro, cyano, trifluoromethyl , or hydroxy; or one of its salts.

[0030] In another implementation, this invention presents the compounds of the formula (I), where R1 is a 5-membered heteroaryl or hydroxy- (C1-C4) alkyl, R2 is hydrogen, or halo, or one of its salts .

[0031] In another implementation, this invention presents the compounds of the formula (I), where R 1 is furanyl, thienyl, pyrrolyl, thiazoyl, imidazolyl, pyridyl, selenophenyl, or pyrazolyl, R 2 is hydrogen or halo, or one of its you go out.

[0032] This invention presents the compounds of the formula I, pharmaceutical compositions using those compounds comprising their pharmaceutically acceptable salts, or one of their pharmaceutically acceptable carriers / excipients, and the methods of use of those compounds.

[0033] Any asymmetric carbon atom in the compounds of this invention can be presented in the configuration (R) -, (S) - or (R, S) -, preferably in the configuration (R) - or (S).

[0034] Any resulting mixture of isomers can be separated based on the physicochemical differences of the constituents, in the isomers, diastereomers, pure geometric or optical racemates, for example, by fractional chromatography and / or crystallization.

[0035] Any racemate resulting from the final or intermediate products can be transformed to the optical amphpods by known methods, for example, by separating their diastereomeric salts, obtained with an optically active acid or base, and releasing the acid or base compound optically. active. Specifically, the hydroxamide or sulfonamide particle could, therefore, be used to convert the compounds of this invention to their optical amphipods, for example, by fractional crystallization of a metal complex (eg, Zn2 +) formed with a co- optically active ligand, for example, L- or D-histidine. Racemic products can also be converted by chiral chromatography, for example, high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0036] It will be appreciated by those with knowledge in the industry that the compounds of the invention that have a chiral center may exist, and be, isolated in optically active and racemic forms. Some compounds may show polymorphisms. It should be understood that this invention encompasses any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof, of a compound of the invention, which has useful properties described herein, and is well known in the industry as preparing optically active forms (by For example, by resolving the racemic form by re-crystallization techniques, by means of the synthesis from optically active starting materials, by a chiral synthesis, or by chromatographic separation using a chiral stationary phase.

[0037] The specific values listed below for radicals, substituents, and ranges, are for purposes of illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents.

[0038] Specifically, (C1-C6) alkyl may be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C1-C6) alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; hydroxy (C1-C6) allcyl can be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1- hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxyphenyl, 1-hydroxyhexyl , or 6-hydroxyhexyl; (C1-C6) alkylthio may be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl,

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triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide ) or quinolyl (or its N-oxide).

[0039] A specific value for R1 is (Ci-C6) alkyl.

[0040] A specific value for R1 is an ethyl.

[0041] A specific value for R1 is an aryl optionally substituted with one or more (Ci-C6) alkoxies.

[0042] A specific value for R1 is a phenyl, 4-fluorphenyl or 4-methoxyphenyl.

[0043] A specific value for R1 is an aryl (Ci-C6) alkyl.

[0044] A specific value for R1 is a benzyl.

[0045] A specific value for R1 is a heteroaryl consisting of furanyl, thienyl, pyrrolyl, thiazoyl, imidazolyl, pyridyl, selenophenyl, or pyrazolyl.

[0046] A specific value for R1 is hydroxy (Ci-C6) alkyl.

[0047] A specific value for Ri is 2-hydroxymethyl.

[0048] A specific value for R2 is halo.

[0049] A specific value for R2 is chlorine.

[0050] A specific value for R2 is fluorine.

[0051] A specific value for R2 is a heteroaryl.

A specific value for R2 is a furanyl or thienyl.

[0052] A specific value for R2 is a phenyl optionally substituted with one or more groups selected from (Ci-C6) alkoxy and (Ci-C6) alkylthio.

[0053] A specific value for R2 is 4-methoxyphenyl or 4-methylthiophenyl.

[0054] A specific group of compounds of the formula I are compounds in which Ri is a heteroaryl selected from furanyl, thienyl, pyrrolyl, thiazoyl, imidazolyl, pyridyl, selenophenyl, or pyrazolyl and R2 is chlorine or fluorine.

[0055] In one implementation of the invention, the compound of formula I excludes compounds in which Ri is an unsubstituted phenyl and R2 is hydrogen.

[0056] The compounds of this invention are useful for inhibiting the growth of tumor / cancer cells or cell proliferation in tumor / cancer cells, slowing the progress of the cell cycle of tumor / cancer cells. Additionally, the compounds of this invention were shown to induce apoptosis. The induction of apoptosis is used as an important method of chemotherapy to treat cancers / tumors. Likewise, the compounds of this invention have valuable pharmaceutical properties, they can be useful as antiproliferative and antitumor / anticancer agents.

[0057] Therefore, in one aspect, the compounds of this invention can be used to inhibit cell proliferation in vitro and in vivo. In one implementation, the compounds of this invention can be used to inhibit cell proliferation in a tumor / cancerous cell by contacting the tumor / cancerous cell with an effective amount of said compounds. In one implementation, the compounds of this invention can be used to treat diseases or conditions of cell proliferation. Such diseases may include, but are not limited to, cancer, autoimmune diseases, fungal diseases, arthritis, graft rejection, inflammatory bowel disease, induced cell proliferation after medical procedures, including, but not limited to, surgeries, angioplasty, and the like.

[0058] In another aspect, the compounds of this invention can be used to inhibit tumor / cancengene growth either in vitro and in vivo. In one implementation, the compounds can be used to inhibit tumor / cancengene growth by contacting the tumor / cancengene cell with an effective amount of said compounds. In one implementation, the invention presents a method for using the compounds of this invention to inhibit tumor or cancengene growth. Tumors or cancers that are treatable according to the methods include, for example, tumors or cancers located in the breasts, in the lungs, in the thyroid, in the lymph node, in the genitourinary system, in the kidneys, in the urethra. , in the bladder, in the

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ovaries, in the testicles, in the prostate, in the musculoskeletal system, in the bones, in the skeletal muscles, in the bone marrow, in the gastrointestinal trachea, in the stomach, in the esophagus, in the small intestine, in the colon , in the rectum, in the pancreas, in the run away, in the smooth muscles, in the central or peripheral nervous system, in the brain, in the spinal cord, in the nerves, in the head, in the neck, in the fingers , in the eyes, in the nasopharynx, in the oropharynx, in the salivary gland, in the cardiovascular system, in the oral cavity, in the tongue, in the larynx, in the hypopharynx, in the soft tissues, in the skin, in the cervix, in the anus, in the retina, and / or in the heart of a mairnfero.

[0059] In one implementation, the compounds of this invention are useful for treating a neoplasic disease, or a tumor / cancer. As used herein, the term "neoplasic disease" refers to any abnormal growth of cells or tissues whether benign (non-cancerous) or malignant (cancerous). Neoplasic diseases that are treatable according to the methods of the invention include, for example, mycoplasmas from acute myelogenous leukemias, chronic lymphocytic leukemias, chronic myelogenous leukemias, cutaneous T-cell lymphomas, hairy cell leukemias and non-Hodgkin lymphomas. .

[0060] Additionally, this invention presents:

- A compound of this invention for use as a medicament;

- The use of a compound of this invention for the preparation of a medicament for the inhibition of cell proliferation in tumor / cancer cells, or the deceleration of the progress of the cell cycle in tumor / cancer cells;

- The use of a compound of this invention for the preparation of a medicament for treating diseases or conditions of cell proliferation;

- The use of a compound of this invention for the preparation of a medicament for inhibiting tumor / cancengene growth in vitro and in vivo;

- The use of a compound of this invention for the preparation of a medicament for treating a neoplasic disease.

- The use of a compound of this invention for the preparation of a medicament for treating a tumor or a cancer.

[0061] The processes for preparing the compounds of formula I are presented as additional implementations of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are presented in previous sections of this document unless they are classified as Another way.

[0062] A compound of the formula I can be prepared as follows.

Chemistry

[0063] Transverse coupling reactions catalyzed by 6-chloro-7- deazapurine riboside palladium 1 (scheme 1, table 1) with boronic acid, zinc, tin and aluminum reagents supplied at 7-deazapurines 6 -substituted protected 2a-I, which are then unprotected by a treatment with 90% aqueous trifluoroacetic acid generating the final free ribosides 3a-31. It should be taken into account that under these conditions acids are also removed to the protective Boc groups of N (record 8) and to trityls (record 10). In the case of the 6-hydroxymethyl derivative (record 12) the benzoyl group is quantitatively deprotected with sodium methoxide in methanol before the final acid deprotection.

Scheme

image4

image5

Ri

image6

rn

TFA / HjO N

image7

HO OH Ja-I

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Table 1. Transverse couplings and unprotections.

 Registry

 R1 R1-M (or M) Product of the transverse coupling (production) Product of the deprotection (production)

 one

   Stage 2 (82%) 3rd (100%)

 2

   ZnCl 2b (93%) 3b (85%)

 4

 XT B (OH) 2 2d (100%) 3d (62%)

 5

 XT 'B (OH) 2 2e (77%) 3e (94%)

 6

 /} SnBu3 2f (93%) 3f (63%)

 7

 lf \ X ~~~ S SnBu3 2g (95%) 3g (88%)

 8

 x> H jO (HOiB g £ ic 2h (76%) 3h (83%)

 9

 X SnBUj 2i (90%) 3i (85%)

 10

 x> N ^ \ BrZn 2j (66%) 3j (93%)

 eleven

 Xx 2k (95%) 3k (83%)

 12

 / OH 21 (54%) to 31 (92%)

 a In addition to the 6-benzoyloxymethyl derivative 21, chromatography also generates a derivative of 6- hi droxymethyl 2l 'with a 23% yield (therefore, a total production of a 77% hydroxymethyl introduction). This product comes from a partial deprotection of the benzoyl group during the aqueous process.

[0064] Other ribosides of 6-hetaryl-7-deazapurine 3m-3s (scheme 2, table 2) are prepared directly from ribosides of 6-chloro-7-deazapurine 4 primarily by the aqueous Suzuki transverse coupling reaction performed under the Shaughnessy conditions (records 1-6) or through the Stille reaction (record 7). In the case of the N-protective triisopropylsilyl particle derived from 3-pyrrolyl, it is unprotected under strong basic conditions of the aqueous coupling (record 3). It should be taken into account that in the case of boronic acids containing NH (records 3, 5, 6) we observe the formation of the arylation of the product of this nitrogen atom by means of the chlorine substitution reaction 4. In the case of the derivative of 4-pyrazolyl (record 6) the subsequent N-arylation and Suzuki reaction lead to a cross linked 5 with 18% production.

Scheme 2

image8

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Table 2. Transverse couplings of free nucleosides 4

 Registry

 Ri Ri-M (or M) Coupling product

 transversal (production)

 one

 P B (OHfc 3m £ 67%)

 2

 and BJOHfc In (69%)

 3

 J '(HG ^ B' 34 (55%)

 4

 and O ^ 6e 3p (64%)

 5

 y o H B £ OH ^ 3q (64%)

 8

   e «, B £ OHk 3r £ 12%) a

 7

 and K. & H SnBuj 3s (51%)

Production not optimized. Dimer 5 (18%), p-D-ribofuranosyl.

image9

[0065] For the preparation of 6-heta ril (aryl) -7-fluoro-7- deazapurine riboside analog transverse couplings, 6-chloro-7-fluoro-7-deazapurine riboside coupling reactions are carried out. O-benzoylates 6 (scheme 3, table 3) to generate 7a-h products that are subsequently deprotected according to Zemplen by supplying 7-fluor 8a-h ribosides.

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image10

image11

Scheme 3

 Registry

 Ri Ri-M (or M) Coupling product Product of the

 transverse (production) deprotection (production)

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[0066] The 3-pyrroMlo 8i derivative is prepared by the Suzuki aqueous reaction of the free 6-chloro-7-fluoro-7-deazapurine riboside 9 with 62% production (scheme 4).

image12

Scheme 4

[0067] The synthesis of the required free riboside 9 begins with the glycosylation of the potassium salt of 4-chloro-5-fluoropyrrolo [2,3-c /] pyrimidine 10 (scheme 5) with halogenose 11 supplying the nucleoside 12 protected with 43% production. Treatment of this nucleoside 12 with aqueous TFA easily generates free nucleoside 9 with 85% production.

image13

TFA-'H ^ Q

eleven

12

image14

Scheme 5

[0068] The synthesis of the compounds in the 7-chloro-7-deazapurine series consists of catalytic cross-coupling reactions of 6,7-dichloro-7-deazapurine riboside 13 (scheme 6, table 4) which they supply acylated products of 6-hetaryl (aryl) 14a-e, which are uniformly deprotected by generating free nucleosides 15a-e.

image15

Scheme 6

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Table 4. Transverse couplings and unprotections

 Registry

 Ri Ri-M (or M) Coupling product Deprotection product

 transversal (production) (production)

 one

 X) E (OH) 2 14a (99%) ISa (91%)

 2

   Q SnBua 14b (99%) 15b (0 &%)

 3

   Q SnESUg. 14c (09%) ISc (94%)

 4

 ; E (OH) 2 14d {QS%> ISd (00%)

 S

     E (OH) 2 14e (92%) 15a (£ 7%)

Salts and hydrates

[0069] The compositions of this invention optionally comprise salts of the indicated aqm compounds, especially non-toxic pharmaceutically acceptable salts containing, for example, Na +, Li +, K +, Ca + 2 and Mg + 2 Those salts may include those derived by the combination of appropriate cations such as alkali earth and alkaline earth metal ions or ammonium and quaternary amino ions with an anion acid molecule, commonly a carboxylic acid. Monovalent salts are preferred if a water soluble salt is desired. Some salts may be useful as intermediates to purify the compounds of formula I or to prepare other salts.

[0070] Metal salts are commonly prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts, which are prepared in this way, are salts containing Li +, Na +, and K +. A less soluble metal can be precipitated from the solution of a more soluble salt by adding the appropriate metal compound. Additionally, the salts may be formed from the acid addition of certain organic and inorganic acids, for example, HCl, HBr, H2SO4, H3PO4 or organic sulfonic acids, to basic centers, commonly amines, or to acyl groups. Finally, it should be understood that the compositions described herein comprise compounds of the invention in their non-ionized forms, as well as zwitterionics, and combinations with stoichiometric amounts of water in hydrates.

[0071] Also included within the approach of this invention are salts of the parent compounds with one or more amino acids. Any of the amino acids aqm described in previous sections of this document are suitable, especially naturally occurring amino acids found in protein components, although the amino acid, commonly, is one that has a side chain with a basic or acidic group, for example , lysine, arginine, or glutamic acid, or a neutral group such as glycine, serine,

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Threonine, alanine, isoleucine or leucine.

Methods to treat cancer

[0072] Another aspect of the invention relates to methods for treating cancer. The compositions of the invention may treat cancer, may act as intermediates for those treatments or have uses as described below. The anti-cancer compounds will bind to locations on the surface or in a cavity of a cancer cell that has a unique geometry for the anti-cancer compound. Compositions that bind to the anti-cancer compound may bind to various levels of reversibility. Those compounds that bind and are substantially irreversible are ideal candidates for use in this method of the invention. Once labeled, linker compositions that are substantially irreversible are useful as probes for cancer detection. Also, the invention relates to methods for detecting cancer in a sample suspected of containing cancer comprising the steps of: treating a sample suspected of having cancer with a composition comprising a compound of the invention linked to a dialing; and observe the effect of the sample on the marking activity. Suitable markings are well known in the diagnostic area, and include radicals, fluorophores, radioisotopes, enzymes, luminescent groups and free and stable chromogens. The aforementioned compounds are labeled in a conventional manner using functional groups such as hydroxyls or aminos.

[0073] Within the context of the invention, samples suspected of having cancer include natural or artificial materials such as living organisms; tissues or cell cultures; biological samples such as samples of biological material (blood, sera, urine, cerebrospinal fluids, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water or air samples; samples of bioproducts such as cell extracts, particularly from recombinant cells that synthesize a desired glycoprotem; and the like Commonly, the sample will be a sample suspected of having cancer. Samples can be contained in any medium including water and organic solvent / water mixtures. The masses include living organisms such as humans, and artificial materials such as cell cultures.

[0074] The treatment step of the invention comprises adding the composition of the invention to the sample or comprising adding a precursor of the composition to the sample. The addition step comprises any method of administration described above.

[0075] If desired, cancer activity after application of the composition can be observed by any method including direct and indirect methods for detecting cancerous activity. All quantitative, qualitative and semi-quantitative methods are contemplated for determining cancengena activity. Commonly, one of the examination methods already described applies, however, any other method such as the observation of the physiological properties of a living organism is also applicable.

[0076] Organisms that have cancer include birds such as humans. The compounds of this invention are useful for the treatment or prophylaxis of cancer in animals or in humans.

[0077] However, when examining compounds capable of treating cancer, it should be kept in mind that the results of enzymatic tests may not correlate with cell culture assays. Therefore, a cell-based test should be the primary examination tool.

Examinations for anti-cancer compounds

[0078] The compositions of the invention are examined to detect their activity against cancer by any conventional technique for evaluating enzymatic activity. Within the context of the invention, the compositions are commonly examined first to detect their activity against cancer in vitro and the compositions that show an activity are then examined for their activity in vivo. Useful in vitro examinations are described in detail, but that will not be explained in this document. However, the examples describe suitable in vitro assays.

Pharmaceutical Formulations

[0079] The compounds of this invention are formulated with conventional carriers and excipients, which will be selected according to ordinary practice. The tablets will contain excipients, sliders, fillers, linkers and the like. Aqueous formulations are prepared in a sterile form, and when they are intended to be administered in a form other than oral administration, they will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkyl methylcellulose, stearic acid and the like. The pH of the formulations

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It ranges from about 3 to about 11, but will usually vary from about 7 to 10.

[0080] Although it is possible for active ingredients to be administered individually, it may be preferred to present them as pharmaceutical formulations. The formulations, whether for veterinary use or for human use, of the invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers, therefore, and, optionally, with other therapeutic ingredients. . The carriers must be "acceptable" in the sense of compatibility with the other ingredients of the formulation and must be physiologically safe for their receptor.

[0081] The formulations include those suitable for the aforementioned routes of administration. The formulations may be conveniently presented in unit dose forms and may be prepared by any of the methods that are well known in the pharmaceutical industry. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Those methods include the step of contacting the active ingredient with the carrier which constitutes one or more accessory type ingredients. In general, the formulations are prepared by uniformly and intimately joining the active ingredient with liquid carriers or with solid carriers divided finely or both, and then, if necessary, shaping the product.

[0082] Formulations of this invention that are suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; such as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as a liquid emulsion of oils in water or a liquid emulsion of water in oil. The active ingredient could be administered as bowling, electuaries or pasta.

[0083] A tablet is made by compression or molding, optionally with one or more accessory type ingredients. The compressed tablets may be prepared by compressing the active ingredient in a suitable machine in a free-flowing form such as a powder or granules, optionally mixed with a binding agent, lubricant, inert diluent, preservative, active surface or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may be coated or labeled and optionally formulated to facilitate a slow or controlled release of their active ingredient.

[0084] For administration to the eye or other external tissues, for example, the mouth and the skin, the formulations are preferably applied in the form of topical ointments or creams containing the ingredient or active clients in an amount of, for example, 0.075 to 20% mass / mass (including the ingredient or active ingredients in a range of 0.1% to 20% in increments of 0.1% mass / mass such as 0.6% mass / mass, 0.7% mass / mass, etc.), preferably between 0.2 to 15% mass / mass and more preferably between 0.5 to 10% mass / mass. When formulated in an ointment, the active ingredients can be used with either a paraffinic or water miscible ointment base. In turn, the active ingredients may be formulated in a cream or an oil-in-water cream base.

[0085] If desired, the aqueous phase of the cream base could include, for example, at least 30% mass / mass of a polyhydric alcohol, that is, an alcohol having 2 or more hydroxyl groups such as propylene glycol, butane 1,3-diol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. Topical formulations may desirably include a compound that improves absorption or penetration of the active ingredient through the skin or other affected areas. Examples of those dermal penetration enhancers include dimethyl sulfoxide and its corresponding analogs.

[0086] The oily phase of the emulsion of this invention could be constituted from known ingredients in a known way. Although the phase could merely comprise an emulsifier (also known as an emulsifier, it desirably comprises a mixture of at least one emulsifier with a gauze or an oil or with a grease and an oil. Preferably, a hydrophilic emulsifier is included together with a hydrophilic emulsifier that acts as a stabilizer.It is also preferred to include an oil and a grease.Together, the emulsifier with or without stabilizers make up the so-called emulsifying wax, and the wax together with the oil and grease make up the called emulsifying ointment that forms the scattered oily phase of cream formulations.

[0087] Suitable emulsifier and emulsion stabilizers for use in the formulation of the invention include Tween® 60, Span® 80, ketosteric alcohol, benzyl alcohol, myrisphilic alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0088] The choice of suitable oils or fats for the formulation is based on obtaining the desired cosmetic properties. The cream should preferably be a product that is not greasy, that does not stain and that can be washed with a consistency suitable to prevent leakage of the tubes or other containers. Mono- or dibasic alkyl esters of straight or branched chains such as di-

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isoadipate, isocetyl stearate, propylene glycol diester or coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture may be used of branched chain esters known as Cromadol CAP, the last 3 being the most preferred. These can be used individually or in combination depending on the required properties. Alternatively, lipids having a high melting point such as soft white paraffin and / or liquid paraffin or other mineral oils can be used.

[0089] Pharmaceutical formulations according to this invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be presented in any form suitable for the proposed method of administration. When used for oral administration, for example, tablets, troches, pills, aqueous or oily suspensions, powders or granules scattered, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions for the purpose of oral use may be prepared according to any method known in the industry for the manufacture of pharmaceutical compositions and those compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and agents. preservatives, to facilitate a preparation with good flavor. Tablets containing the active ingredient in a mixture with a pharmaceutically acceptable excipient that is not toxic that is suitable for the manufacture of tablets is acceptable. These excipients could be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch, or almic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be covered or not covered by known techniques that include microencapuslation to delay disintegration and absorption in the gastrointestinal trachea and, therefore, facilitate sustained action for a longer period. For example, a time delay material such as glyceryl monostearate or a glyceryl diaestearate may be used individually or with a wax.

[0090] Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or caolm, or as soft gelatin capsules where the active ingredient is mixed with water or in an oily medium, such as walnut oil, liquid paraffin or olive oil.

[0091] The aqueous suspension of the invention contains the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Those excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum, and dispersing or humidifying agents such as phosphatides that occur naturally (for example, lecithin), a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (for example , heptadecaethylene oxyethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and anhydrous hexitol (for example, a polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

[0092] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or catholic alcohol. Sweetening agents, such as those already mentioned, and flavoring agents may be added to facilitate an oral preparation with a good taste. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

[0093] Powders or granules that can be spread of the invention suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in a mixture with a dispersing agent or humectants, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents were listed as examples in previous sections of this document. Additional excipients may also be present, for example, sweetening, flavoring and coloring agents.

[0094] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase could be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or one of these mixtures. Suitable emulsifying agents include naturally occurring gums, such as acacia gum and tragacanth gum,

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naturally occurring phosphatides, such as soy lecithin, esters or partial esters derived from fatty acids and anhydrous hexitol, such as sorbitan monooleates, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate . The emulsion may also contain flavoring and sweetening agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol and sucrose. Those formulations may also contain a demulcent, preservative, flavoring or coloring agent.

[0095] The pharmaceutical compositions of the invention could be in the form of a sterile injectable preparation, such as an aqueous or oleaginous suspension. The suspension could be formulated according to methods known in the industry using suitable thickening or wetting agents and suspending agents already mentioned herein. The sterile injectable preparation could also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane diol or prepared with a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and an isotonic sodium chloride solution. Additionally, sterile and fixed oils can be conventionally used as solvents or suspending media. To this end, any soft fixed oil may be used including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid can be used in the same way in the preparation of injectables.

[0096] The amount of the active ingredient that may be combined with a carrier material to produce an individual dose form will vary depending on the condition being treated and the particular mode of administration. For example, a release formulation over time that has the purpose of oral administration to humans could contain about 1 to 1000 mg of the active material combined with an appropriate and convenient amount of the carrier material that may vary from about 5 to about 95% of the total compositions (mass: mass). The pharmaceutical composition could be prepared to facilitate easily measurable amounts for administration. For example, an aqueous solution that has the purpose of being administered in intravenous infusions could contain from about 3 to 500 µg of the active ingredient per milliliter of the solution for infusions of a suitable volume to occur at a rate of about 30 ml. /hour.

[0097] Formulations suitable for administration to the eyes include eye drops where the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in those formulations at a concentration of 0.5 to 20%, advantageously from 0.5 to 10% and particularly at about 1.5 percent mass / mass.

[0098] Formulations suitable for topical administration in the mouth include pills containing the active ingredient in a seasoned form, usually sucrose and acacia or tragacanth; pills comprising the active ingredient in an inert form such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0099] Formulations for rectal administration may be presented as suppositories with a suitable base comprising, for example, cocoa butter or salicylate.

[0100] Formulations suitable for intra-pulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range of between 0.1 and 500 microns in such increments such as 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalations through the nasal pass or by inhalations through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active invention. Formulations suitable for administration by aerosol or by dry powders may be prepared according to conventional methods and may be administered with other therapeutic agents such as the compounds used so far in the treatment or prophylaxis of cancerous infections as described below.

[0101] Formulations suitable for vaginal administration may be presented as formulations in pessaries, buffers, creams, gels, pastes, foams or aerosol that additionally contain the active ingredient to those carriers such as those considered in the industry as suitable.

[0102] Formulations suitable for parenteral administration include sterile aqueous and non-aqueous injection solutions that may contain antioxidants, buffers, bacteriostatics and solutes that cause the formulation to become isotonic with the blood of the desired recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickening agents.

[0103] The formulations are presented in single-dose or multi-dose containers, for example, sealed ampoules and flasks, and may be stored in a dry frozen (lyophilized) condition that requires only the addition of the sterile liquid carrier, for example, water for injections, immediately

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Before its use. Solutions and suspensions of extemporaneous injection are prepared from powders, granules and sterile tablets of the type described above. Preferred unit dose formulations are those containing a daily dose or several daily unit partial doses, as mentioned herein, or one of its appropriate fractions, of the active ingredient.

[0104] It should be clear that in addition to the ingredients mentioned specifically in previous sections of this document, the formulations of this invention may include other conventional agents in the industry that correspond to the type of formulation in question, for example, those suitable for administration. Oral may include flavoring agents.

[0105] The invention further provides veterinary compositions comprising at least one active ingredient as defined above together with, therefore, a veterinary carrier.

[0106] Veterinary carriers are useful materials that are intended to be administered to the composition and may be solid, liquid or gaseous materials that are inert otherwise or that are acceptable in the veterinary industry and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

[0107] The compounds of the invention may also be formulated to facilitate a controlled release of the active ingredient to allow a less frequent dose to improve the pharmacokinetic or toxicity profile of the active ingredient. Likewise, the invention also presents compositions comprising one or more compounds of the invention formulated for controlled or sustained release.

[0108] The effective dose of the active ingredient depends on, at least, the nature of the condition being treated, the toxicity, whether the compound is being used prophylactically (smaller doses) or against an active cancerous infection, the method of administration, and the pharmaceutical formulation, and will be determined by the clinical worker using dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg / kilogram of body mass per day. Commonly, from about 0.01 to about 10 mg / kilogram of body mass per day. More commonly, from about 0.01 to about 5 mg / kilogram of body mass per day. More commonly, from about 0.05 to about 0.5 mg / kilogram of body mass per day. For example, the daily candidate dose for an adult human of approximately 70 kg of body mass will vary from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and could take the form of single or multiple doses.

Administration Routes

[0109] One or more compounds of the invention (referred to herein as active ingredients) are administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) routes, and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient. An advantage of the compounds of this invention is that they are bio-available orally and can be administered orally.

Combination therapy

[0110] The active ingredients of the invention may also be used in combination with other active ingredients. Those combinations are selected based on the condition being treated, cross-activity of ingredients and pharmacological properties of the combination. For example, when treating cancer, the compositions of the invention can be combined with other chemotherapeutic agents. The 2nd chemotherapeutic agent can be any suitable compound that has a biological activity against one or more forms of cancer.

[0111] It is also possible to combine any compound of the invention with one or more active ingredients in a unit dose form for simultaneous or sequential administration to cancer patients. Combination therapy could be administered in a simultaneous or sequential regimen. When administered sequentially, the combination could be administered in 2 or more administrations. The 2nd and 3rd active ingredients in the combination may have chemotherapeutic activities and may include any of the additional chemotherapeutic agents described herein. Example active ingredients will be administered in combination with compounds of the invention as described below.

[0112] Additional suitable chemotherapeutic agents include, for example, anthracyclines (for example, doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone); (b) other DNA interleavers (for example, actinomycins C, D, B, etc.); podophyllotoxins and epipodophyllotoxins (the etoposide, teniposide, ctoposide)); (c) alkylating agents (for example, mechlorethamine, melphalan, cyclophosphamide, chlorambucil, ifosfamide, gliadel implants, lomustine, busulfan, dacarbazine, cisplatin, carboplatin, oxaliplatin, iproplatin, and the

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tetraplatin); (d) hormonal agents (for example, antiestrogen / estrogen antagonists (tamoxifen and other SERMs); LHRH agonists and antagonists (leuprolide acetate, goserelin, abarelix); aromatase inhibitors; and antiandrogens; (e) chemoprevention agents ( for example, NSAIDs and cis-retinoids) and (f) chemopreventive agents of the cell cycle.

[0113] In turn, the additional chemotherapeutic agent could include, for example, antineoplasts. Representative antineoplasts include, for example, complemented (for example, levamisole, gallium nitrate, granisetron, estonian-89 sargamostim chloride, filgrastim, pilocarpine, dexrazoxane, and ondansentron); androgen inhibitors (for example, flutamide and leuprolide acetate); antibiotic derivatives (for example, doxorubicin, bleomycin sulfate, daunorubicin, dactinomycin and idarubicin); antiestrogens (for example, tamoxifen citrate, its analogs, and non-steroidal antiestrogens such as toremifene, droloxifene, and roloxifene); antimetabolites (for example, fludarabine phosphate, recombinant interferon alfa-2b, sodium methotrexate, plicamycin, mercaptopurine and thioguanine); cytotoxic agents (for example, doxorubicin, carmustine [BCNU], lomustine [CCNU], USP of cytarabine, cyclophosphamide, stamucin sodium phosphate, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin , busulfan, cyclophosphamide, mitoxantrone, carboplati, cisplati, cisplatin, recombinant interferon alfa-2a, paclitaxel, teniposide, and streptozocin); hormones (for example, medroxyprogesterone acetate, estradiol, megestrol acetate, octeotide acetate, diethylstilbestrol diphosphate, testolactone and goserelin acetate); immunomodulators (for example, aldesleucine); Nitrogen mustard derivatives (for example, melphalan, chlorambucil, mechlorethamine, and thiotepa) and steroids (betametsone sodium phosphate and betamethasone acetate).

[0114] Suitable additional chemotherapeutic agents include, for example, alkylating agents, antimitotic agents, plant alkaloids, biological agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and synthetic elements.

[0115] Representative alkylating agents include, for example, asaley, AZQ, BCNU, busulfan, bisulfan, carboxyphthalatoplatin, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cis-platinum, clomazone, cyanomorpholinodoxorubicin, cycloddodolacthododoctiodoctone, cycloddodolacthododactiodoctone, cycloddodolacthodoctone, cyclodonactophodolacthododactone, cyclodonactophodolacthododactone, cyclodonacthodopanedioctone, cyclodonacthodopanedioctone, cyclodonacthodopanedioctone, cyclodonacthodopanedioctone, cyclodonactophodolacthododactophodolacthododacthodopanediocyanide hepsulfan, hicantone, ifosfamide, melphalan, methyl CCNU, mitomycin C, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazinedione, pipobroman, porphyromycin, spirohydantoma mustard, streptozocin, teroxyrone, thiolatin, tetrapatin, tetrapatin, tetrapatin, tetrapatin uracil nitrogen mustard and Yoshi-864.

[0116] Representative antimitotic agents include, for example, alocolchichna, halicondrine B, colchicine, colchicine derivatives, dolastatin 10, maitansin, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, the cystem of trityl, vinblastine sulfate, and vincristine sulfate.

[0117] Representative plant alkaloids include, for example, actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mitramycin, mitomycin, daunorubicin, VP-16-213 , VM-26, navelbina and taxotere.

[0118] Representative biological elements include, for example, interferon alfa, BCG, G-CSF, GM-CSF, and interleukin-2.

[0119] Representative topoisomerase I inhibitors include, for example, camptotecinam camptothecin derivatives, and morpholinodoxorubicin.

[0120] Representative topoisomerase II inhibitors include, for example, mitoxantrone, amonafide, m-AMSA, antrapirazole derivatives, pyrazoloacridine, bisantrene HCL, daunorubicin, deoxidexorubicin, menogaril, daunomycin de N, N-Decilyl, oxantrazole, rubidazone, le VM-26 and VP-16.

[0121] Representative synthetics include, for example, hydroxyurea, procarbazine, o, p'-DDD, dacarbazine, CCNU, BCNU, cis-diaminochloroplatin, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, holo-transretinoic acid, gliadel and sodium porffmero.

[0122] In turn, the additional chemotherapeutic agent may include drugs that bind tubulin and medications that affect the dynamics and functioning of tubulin. This includes a variety of medications that are not chemically related to vinca alkaloids or taxanes (for example, CP-248 [a derivative of Exisulind] and ILX-651). These medications have distinctive effects on the cells in the G2M phase and may have functionally independent effects of the cells in the G1 and / or S phases.

[0123] In turn, the additional chemotherapeutic agent may include selective apoptotic anti-cancer drugs (SAANDs) that include sulindac, aptosyn, CP-461, CP-248 and related sulindac-derived compounds that inhibit a or more of the following GMP ctelica phosphodiesterase isoenzymes (cGMP PDE): 1, 2, 5.

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[0124] In turn, the additional chemotherapeutic agent may include medications that inhibit proteasomes (bortezomib or Velcade). Proteasomes degrade many ubiquitin-labeled proteins that are marked for active destruction. Ubiquitin-labeled proteins may include critical regulatory molecules of the cell cycle and molecules that regulate apoptosis at specific stages of the cell cycle. Although proteasomes may degrade proteins throughout the cell cycle, proteases degraded by proteasomes include some more critical regulatory proteins of the cell cycle. The so-called "active cell cycle logic" could be applied to the treatment of diseases in several categories, including cancer, inflammatory / autoimmune diseases, and neurological diseases that involve the cell cycle and / or apoptosis in a disorderly manner.

[0125] In turn, the additional chemotherapeutic agent may include drugs that inhibit heat shock protein 90 (HSP90 - heat shock protein 90), a 'chaperone protein' that participates in the degradation of 'client' proteins in the ubiquitin-mediated proteasome path. Some medications seem to exert their antitumor effect by inhibiting the intimate activity of the HSP90 ATPase, resulting in the degradation of the HSP90 "customer protection" through the ubiquitin proteasome path. Examples include: geldanamicin, 17-allylamino geldanamicin, 17-demethoxyigeldamicin and radicicol.

[0126] Biological agents that depend on cell cycle or biological agents that depend on suitable schedules include drugs, proteins or other molecules that block, impede, or otherwise interfere with the progress of the cell cycle in phase G1, at the interface Gl / S, in the S phase, in the G2 / M interface, or in the M phase of the cell cycle. These medications depend on the cell cycle or depend on schedules.

[0127] Specifically, suitable biological agents that depend on cell cycle or that depend on schedules include:

(1) Uridine nucleotide analogs, thymidine nucleoside analogs, and uridine and thymidine nucleoside analogs. These compounds act in the S phase in tumor cells, and possibly in neovascular endothelial cells. These compounds include, for example, 5-fluorodeoxyuridine (floxuridine, FUDR); 5-fluorouracil (5-FU); pro-5-FU medications (for example, capecitabine, 5'-deoxy-5-fluorouridine, ftorafur, flucytosine); bromodeoxyuridine; and iododexoyuridine.

(2) Fluoropyrimidine modulators. These compounds act in the S phase in tumor cells, and possibly in neovascular endothelial cells. These compounds include, for example, leurovorin, methotrexate and other folates; levamisole; acivicin; phosphonacetyl-L-aspartic acid (PALA - phosphonacetyl-L-aspartic acid); the brequinar; 5-ethynyluracil; and the uracil.

(3) Cytidine analogues and cytidine nucleoside analogs. These compounds act in the S phase in tumor cells, and possibly in neovascular endothelial cells. These compounds include, for example, cytarabine (Ara-C, cytosine arabinoside); gemcitabine (2 ', 2'-difluorodeoxycytidine); and 5-azacitidine.

(4) Purine analogs and purine nucleoside analogs. These compounds act in the S phase in tumor cells, and possibly in neovascular endothelial cells. These compounds include, for example, 6-thioguanine; 6-mercaptopurine; azathioprine; adenosine arabinoside (Ara-A-adenosine arabinoside); 2 ', 2'-difluorodeoxyguanosine; deoxicoformicin (pentoestatin); cladribine (2-chlorodeoxyadenosine); and adenosine deaminase inhibitors. 5 * * * * *

(5) Anti-folates. These compounds act in the S phase in tumor cells, and possibly in

neovascular endothelial cells. These compounds include, for example, methotrexate; the

aminopterin; trimetrexate; edatrexate; N10-propargil-5,8-dideazafolic acid (CB3717); ZD1694, 5,8-dideazaisopholic acid (IAHQ); 5,10-dideazatetrahydrofolic acid (DdAtHF); he

5-deazafolic acid (substrate deficient for FPGS); PT523 (N alpha- (4-amino-4-deoxiptroyl) -N delta-hemiftaloyl-L-ornithine); 10-ethyl-10-deazaaminopterin (DDATHF, lomatrexol); the piritrexim; 10-EDAM; ZD1694; GW1843; PDX (10-propargil-10-deazaaminopterin); the folate of multiple objectives

(ie, LY231514, permetrexed); any inhibitors based on thymidylate synthase folates (TS-thymidylate synthase); any inhibitor that relies on folates or reductases of

dihydrofolates (DHFR - dihydrofolate reductase); any inhibitor that is based on glycinamide ribonucleotide transformilase folates (GARTF - glycinamide ribonucleotide transformylase); any follicpolyglutamate synthetase inhibitor (FPGS - folylpolyglutamate synthetase); and any inhibitor based on GAR formyl folates or transferases (AICAR transformilase).

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(6) Other anti metabolites. These compounds act in the S phase in tumor cells, and possibly in neovascular endothelial cells. These compounds include, for example, hydroxyurea and polyamines.

(7) Specific S-phase radiotoxins (deoxythymidine analogs). These compounds act in the S phase in all cells that undergo a DNA synthesis. The compounds are incorporated into chromosomal DNA during the S phase. These compounds include, for example, [125I] -iododeoxyuridine; [123I] -iododeoxyuridine; [124I] -iododeoxyuridine; [80mBr] - iododeoxyuridine; [131I] -iododeoxyuridine; and [211At] -astatin-deoxyuridine.

(8) Enzyme inhibitors involved in deoxynucleoside / deoxynucleotide metabolism. These compounds act in the S phase in tumor cells, and possibly in vascular endothelial cells. These compounds include, for example, thymidylate synthase inhibitors (TS-thymidylate synthase); dihydrofolate reductase inhibitors (DHFR - dihydrofolate reductase); glycinamide ribonucleotide transformialase inhibitors (GARTF - glycinamide ribonucleotide transformylase); Folylpolyglutamate synthetase inhibitors (FPGS - folylpolyglutamate synthetase); GAR formyl transferase inhibitors (AICAR transformilase); DNA polymerase inhibitors (Pol in DNA; for example, afidocillin); ribonucleotide reductase inhibitors (RNR-ribonucleotide reductase); thymidine kinase inhibitors (TK-thymidine kinase); and topoisomerase I enzyme inhibitors (for example, camptothecins, irinotecan [CPT-11, camptosar], topotecan, NX-211 [lurtotecan], rubitecan, etc.).

(9) Nucleoside analogs that terminate DNA strands. These compounds act specifically in the S-phase cells and are incorporated into the chromosomal DNA during the S-phase; and end the growing strand of DNA. These compounds include, for example, acyclovir; abacavir; valacyclovir; zidovudine (AZT); didanosine (ddl, dideoxycytidine); zalcitabine (ddC); stavudine (D4T); lamivudine (3TC); any analog of the 2'3'-dideoxy nucleosides; and any analogue of the 2'3'-dideoxy nucleosides that terminate the DNA synthesis. These compounds include, for example, inhibitors of growth factor receptor tyrosine kinases that regulate progression through the G1 phase, the Gl / S interface or the S phase of the cell cycle (eg, EGF receptors , HER-2 neu / c-erbB2 receptors, PDGF receptors, etc. [eg, trastusumab, iressa, erbitux, tarceval]); non-receptor tyrosine kinase inhibitors (for example, the c-src family of tyrosine kinases; [eg gleevec]); serine-threonine kinase inhibitors that regulate progression through the G1 phase, the G1 / S interface or the S phase of the cell cycle (for example, cyclin-dependent kinases of G1, cyclin-dependent kinases of G1 / S and the cyclin-dependent kinases of S [eg, CDK2, cDK4, CDK5, CDK6]; mitogen activated kinases; MAP kinase signaling pathways); phase G1, G1 / S interface or phase cyclin inhibitors [eg, cyclin D1, D2, D3, E, and A]); G-protein and cGMP phosphodiesterease inhibitors that positively regulate cell cycle progression in the G1 phase, at the G1 / S interface or in the S phase of the cell cycle; drugs that inhibit the induction of early and immediate response transcription factors (eg, c-jun kinase of the N-terminal, c-myc); and drugs that inhibit proteasomes that degrade the regulatory molecules of the 'negative' cell cycle (for example, p53, p27 / Kip1; [eg, bortezomib]).

(10) Cytokines, growth factors, anti angiogenic factors and other proteins that inhibit the progress of the cell cycle in the G1 phase or at the G1 / S interface of the cell cycle. These compounds act in the G1, G1 / S, or S phase of the cell cycle in tumor cells, and in some cases, in neovascular endothelial cells. These compounds include, for example, interferons; interleukins; somatostatins and somatostatin analogs (octreotides, the sandoestatin LAR); and many anti-angiongenic factors inhibit cell proliferation of endothelial cells in the G1 or G1 / S phases of the cell cycle. eleven

(11) Medications and compounds that inhibit the progress of the cell cycle at the G2 / M interface, or at the M phase of the cell cycle. These compounds act at the G2 / M interface or at the M phase of the cell cycle in tumor cells, and in some cases, in neovascular endothelial cells. These compounds include, for example, (a) drugs directed to micro tubules-taxanes (for example, taxol, taxotere, epothilones, and other taxanes and derivatives); (b) drugs directed to vinca micro-tubular alkaloids (for example, vinblastine, vincristine, vindesine; vinflunine, vinorelbine, vinzolidine, nocadazole and cochicines); (c) drugs directed to micro tubules - others (for example, stratomustine, CP-248 and CP-461); (d) serine threonine kinase inhibitors that regulate progress through the G2 / M interface or the M phase of the cell cycle (for example, kinase inhibitors that depend on the G2 / M cyclin (for example, CDC2); M-phase cyclin inhibitors (for example, cyclin B) and any medications that block, impede or otherwise interfere with the progress of the cell cycle at the G2 / M interface or at the M phase

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cellular cycle).

(12) Useful radiopharmaceutical elements in therapies and / or diagnosis of radiation. An appropriate class of radioisotope decay through a nuclear decay process known as the "Auger Process" or the "Auger Sequence". Auger emitting isotopes generate short-acting electrons that efficiently divide duplex DNA. Suitable Augers emitting radionuclides include, for example, 125-iodine, 123-iodine and 80m-bromine. Suitable suitable nucleosides of halogenated pyrimidine and purine include, for example, 5-125 iodo-2'- deoxyuridine, 5-123yodo-2'-deoxyuridine, 5-80mBromo-2'-deoxyuridine and 8-80mBromo-2 '- guanidine.

Growth factors

[0128] Many growth factors and cytokines have the ability to stimulate malignant cells to cross specific points in the cell cycle. For example, G-CSF or GM-CSF can stimulate leukemic blasts in acute myelogenous leukemia to cross the G1 / S interface. This increases the susceptibility of the cells to specific cell cycle medications, such as cytarabine. Similar strategies were previously examined using EGF or cytotoxic drugs for solid tumors. To respond to the growth factor, the cells must be at a specific stage of the cell cycle, for example, at the G1 / S interface. The continued presence of a growth factor could be beneficial, since, at any time, only a subset of blasts are in the G1 / S. Therefore, growth factors act in a cell cycle in a specific way. A similar logic can be applied to the use of hematopoietic growth factors used to treat neutropenia, anemia and thrombocytopenia.

[0129] As such, peptide / protein growth factors can be used in this invention to promote the survival of non-malignant cell lineages. A benefit of using these substances is the ability to protect proliferating cells in the bone marrow, skin, gastrointestinal and oral mucosa, and hair follicles.

[0130] Examples of substances within this category include, for example, hematopoietic growth factors: G-CSF, GM-CSF, erythropoietin, thromboplastin and biologically active derivatives of these peptides; keratinocyte growth factor (KGF - keratinocyte growth factor) for mucositis; the B-lymphocyte stimulating pepdie (BLys); platelet derived growth factor (PDGF), epithelial growth factor (EGF), TGF-alpha and related growth factors; interleukins (for example, IL-2, IL-6); and other cytokines, growth factors and peptides that stimulate the proliferation of non-malignant cells that must be protected.

Growth factors / therapeutic cytokines

[0131] Some growth factors / therapeutic cytokines may inhibit cell proliferation of cancerous cells and / or neovascular cells at specific stages of the cell cycle. For example, interferons, somatostatins, octreotides and their analogs, thrombospondin and troponin-I inhibit the proliferation of neovascular endothelial cells by reducing the rate at which cells enter the S phase. As such, one or more of these Substances can be used in this invention.

[0132] Combination therapy could facilitate a “synergy” and a “synergistic effect”, that is, the effect achieved when active clients are used together is greater than the sum of the effects that result from the use of compounds by separated. The synergistic effect could be achieved when the ingredients are: (1) co-formulated and administered or used simultaneously in a combined formulation; (2) administered alternately or in parallel as separate formulations; or (3) by any other regime. When administered in an alternating therapy, the synergistic effect could be achieved when the compounds are administered or delivered sequentially, for example, in separate tablets, pills or capsules, or by different injections into different syringes. In general, during alternation therapy, an effective dose of each active ingredient is administered sequentially, that is, in series, while, in a combination therapy, effective doses of 2 or more active ingredients are administered together.

Metabolites of the compounds of the invention

[0133] 2 in vivo metabolic products of the compounds described herein are also classified within the scope of this invention. Those products could result from, for example, oxidation, reduction, hydrolysis, amidation, esterification and the like of the compound administered, mainly due to enzymatic processes. Also, the invention includes compounds produced by a process that comprises contacting a compound of this invention with a controller for a period of time sufficient to generate the corresponding metabolic product. Those products are commonly identified by preparing a radiologically labeled compound (eg, C14 or H3) of the invention, administering it.

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parenterally in a detectable dose (for example, a dose greater than about 0.5 mg / kg) to an animal such as a rat, a mouse, a guinea pig, a monkey or a man, allowing sufficient time for Run the metabolism (usually between 30 seconds to 30 hours) and isolate your conversion products from urine, blood or other biological samples. These products are easily planed since they were labeled (others are planed by the use of antibodies capable of binding to epitopes that survive in the metabolite). The metabolite structures are determined in a conventional manner, for example, by MS or NMR analysis. In general, metabolite analysis is performed in the same way as metabolic studies of conventional medications that are well known to people with knowledge in the industry. Conversion products, as long as they are not in vivo, are useful in diagnostic tests to establish therapeutic doses of the compounds of the invention even if they do not possess any anti-cancer activity per se.

[0134] Recipes and methods for determining the stability of compounds in substitute gastrointestinal secretions are well known. The compounds are defined herein as stable in the gastrointestinal trachea when less than about 50% moles of the protected groups are unprotected in the intestinal or gastric substitute juices with an incubation of one hour at 37 ° C. The fact that the compounds are stable to the gastrointestinal trachea does not necessarily mean that they cannot be hydrolyzed in vivo.

[0135] In an implementation of the invention, the compound is in an isolated and purified form. Generally, the term "isolated and purified" refers to the compound being in a form substantially free of biological materials (eg, blood, tissues, cells, etc.). In a specific implementation of the invention, the term refers to the compound or conjugation of the invention being free of biological materials in about 50% of its mass; In another specific implementation, the term refers to that 75% of the mass of the compound or conjugate of the invention is free of biological materials; and in another implementation, the term refers to the fact that 90% of the mass of the compound or conjugate of the invention is free of biological materials; In another specific implementation, the term refers to 98% of the mass of the compound or conjugate of the invention being free of biological materials; and in another implementation, the term refers to the fact that 99% of the mass of the compound or conjugate of the invention is free of biological materials. In another specific implication, the invention presents a compound or conjugate of the invention that was prepared synthetically (eg, ex vivo).

[0136] The anti-cancer cavity of a compound could be determined using pharmacological models that are well known in the industry, or using an A test described below.

Test A: cytostatic cell culture assay (Glsn)

[0137] This assay is based on the quantification of cell counts by a chlorometric detection of the proteins associated with cells. This assay is based on the ability of sulphordamine B (SRB) to bind to cell protein components that are attached to tissue culture plates by trichloroacetic acid (TCA - trichloroacetic acid). SRB is a bright pink aminoxanthene dye with 2 symphonic groups that bind to basic amino residues under moderately acidic conditions, and dissociate under basic conditions. Due to the stoichiometric link of the SRB, the amount of dye extracted from the stained cells is directly proportional to the cell mass.

[0138] Cellular lines: all cell lines were obtained from ATCC (Manassas, VA). Culture media containing Glutamax and trypsin were purchased from Invitrogen (Carlsbad, CA). Doxorubicin, Clofarabine, TCA and SRB came from Sigma-Aldrich (St. Louis, MO). Gemcitabine was obtained from Moravek Biochemicals (Brea, CA).

Test protocol:

[0139]

1. Keep the cell lines in the medium listed in Table 1. Triple the subconfluent cells, count them and adjust the cell concentrations according to the cell counts listed in Table 1.

2. Distribute the cells in 96-well plates in 150 pl of media. Incubate the plate overnight in a humidified CO2 incubator at 37 ° C. 3

3. Fix a plate of each cell line with TCA. Discard the culture medium of the plates by gently tapping them and adding 100 pl of 10% (volume / volume) of TCA fno to each well. Incubate the plates in a 4 ° refrigerator for one hour. Discard the TCA from the plates by tapping them gently. Rinse the plates 4 times in a sink containing tap water. Store the plates at room temperature. These plaques represent cell counts on day zero.

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4. Prepare a set of media solutions containing at various concentrations of the compounds examined by making serial dilutions of 5 times in 96-well plates. Add 50 | j | of the diluted compounds in each well. Include controls with untreated cells and cells treated with doxorubicin, clofarabine and gemcitabine.

5. Incubate the plates for 5 days at 37 ° C.

6. Fix the plates with TCA. Discard the culture medium of the plates by tapping them lightly and add 100 jl of 10% (volume / volume) of TCA fno to each well. Incubate the plates in a refrigerated at 4 ° for one hour. Discard the TCA from the plates by tapping them gently. Rinse the plates 4 times in a sink containing tap water.

7. Remove excess water by gently knocking the plates upside down on a paper towel. Allow the plates to air dry at room temperature.

8. Add 100 microliters of 0.057% of a SRB solution in 1% (volume / volume) of acetic acid to each well of the plates fixed with TCA on day 0 and 5. Leave them at room temperature for 30 minutes

9. Tap the plates gently to discard the SRB. Rinse the plates 4 times with 1% (volume / volume) of acetic acid.

10. Store the plates in an incubator at 37 ° C to facilitate faster drying.

11. Once the plates are completely dry, add 200 µl of 10 mM of a Tris base solution (pH 10.5) to each well. Leave them at room temperature for 30 minutes to solubilize in the SRB.

12. Measure the OD at 500 nm in the microplate reader.

13. Calculate the percentage of cell growth inhibition using the following formula:

% of cell growth in control 0 100x (OD sample - mean OD day q) / (OD negative control - OD average day 0)

[0140] For the determination of Gl50, draw dose response curves between the concentration of the compound and the percentage of growth inhibition. Gl50 values can be derived by adapting to dose response curves using the sigmoid dose response equation.

 Cellphone line

 Medium Sowing density Dissociation agent

 HCT 116 - Colon

 RPMI, 10% FBS, 1X Pen / Strep 800 cells / Trypsin well

 HCT 15 - Colon

 RPMI, 10% FBS, 1X Pen / Strep 1600 cells / Trypsin well

 BT549

 RPMI, 10% FBS, 1X Pen / Strep 4000 cells / Tryple Express well (Invitrogen)

 HS 578 - Mama

 RPMI, 10% FBS, 1X Pen / Strep 4000 cells / Tryple Express well (Invitrogen)

 PC3 - Prostate

 F12K, 10% FBS, 1X Pen / Strep 2500 cells / Trypsin well

 DU145 - Prostate

 MEM, 10% FBS, 1X Pen / Strep 800 cells / Trypsin well

 H23 - Pulmon

 RPMI, 10% FBS, 1X Pen / Strep 6000 cells / Trypsin well

 A549- Pulmon

 RPMI, 10% FBS, 1X Pen / Strep 1500 cells / Trypsin well

[0141] Representative compounds of the invention commonly have activities against one or more of the cell lines just mentioned with a Gl50 of less than about 20 jm. Some representative compounds of the invention have activities against one or more of the cell lines just mentioned with a Gl50 of less than about 1 jm. Other representative compounds of the invention have an activity against one or more cell lines just mentioned with a Gl50

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less than about 0.1 pm.

[0142] Data of representative compounds of the test invention are shown in the table below.

Table 1

 G150 (pM)

 Lung

 Prostate Colon Mama Hs578

 A549

 NCIH23 Du145 PC3 HCT116 HCT15 Hs578

 Example 1

 4,404 1,242 2,560 4,684

 Example 2

 > 20 15,708> 20> 20

 Example 3

 > 20 1,306> 20> 20

 Example 4

 > 20 0,729> 20 2,522

 Example 5

 0.088 4.198 0.007 0.091 0.078 0.020 0.049

 Example 6

 0.045 4,100 0.009 0.067 0.049 0.078 0.101

 Example 7

 > 20 2,505 0.630 1,275> 20 2,436 1,275

 Example 8

 0.409 4.399 0.019 0.104 0.484 0.208 0.294

 Example 9

 2,594 2,490 0,094 0,194 3,690 0,224 1,942

 Example 10

 > 20> 20> 20> 20> 20> 20> 20

 Example 11

 0.222 0.028 0.030 0.052 0.447 0.030 0.053

 Example 12

 0.073 0.697 0.036 0.150 0.092 0.086 0.264

 Example 13

 0.627 4.240 0.032 0.092 0.216 0.098 0.711

 Example 14

 0.365 2,319 0,030 0.384 0.500 0.163 0.442

 Example 15

 0.230 2.518 0.028 0.012 0.342 0.005 0.290

 Example 16

 3,251 3,226 0.409 0.560 7.314 1.061 3.937

 Example 17

 6,233 5,226 0,075 0,427 5,685 0.674 3,056

 Example 18

 4,858 0.387> 20> 20

 Example 19

 12,854 0,581> 20 19,150

 Example 20

 0.109 4.302 0.005 0.075 0.039 0.057 0.175

 Example 21

 0.061 4,700 0.009 0.083 0.009 0.018 0.132

 Example 22

 0.195 2.607 0.009 0.176 0.453 0.111 0.315

 Example 23

 0.060 4.637 0.005 0.087 0.018 0.039 0.177

 Example 24

 0.399 2.950 0.066 0.105 0.145 0.179 0.813

 Example 25

 0.902 4.983 0.024 0.175 1,265 0.361 0.566

 Example 26

 > 20 7,620 0,887 2,113> 20 3,591 2,113

 Example 27

 0.126 1.597 0.010 0.060 0.255 0.065 0.356

 Example 28

 2,468 5,016 0,138 0,263 1,417 0,290 13,175

 Example 29

 15,190 13,230 10,000> 20> 20 8,146> 20

 Example 30

 0.375 2.016 0.013 0.035 0.275 0.081 1.643

 Example 31

 1,052 5,259 0.054 1,203 1,961 0.632 1,582

 Example 32

 0.378 4.538 0.018 0.118 0.101 0.148 0.109

[0143] Representative compounds of the invention were also shown to inhibit mycobacterial adenosine kinase. Also, in one implementation, the invention also presents a method for inhibiting an adenosine kinase (eg, mycobacterial adenosine kinases) which comprises contacting the adenosine kinase with a compound of formula I or a pharmaceutically salts thereof. acceptable.

[0144] In another implementation, the invention also presents a method for treating a disease associated with the activity of adenosine kinases in an animal that comprises administering to said animal (eg, a mammalian such as a human) that needs that therapy, at an effective amount of adenosine kinase inhibitor of a compound of formula I or a pharmaceutically acceptable salt thereof. Diseases associated with the activity of adenosine kinases may include inflammations, sepsis, arthritis, rheumatoid arthritis, osteoarthritis, autoimmune diseases, burns, adult respiratory interruption smdrome, inflammatory bowel smdrome, necrotizing enterocolitis, lung diseases chronic obstructive, psoriasis, conjunctivitis, iridocyclitis, ischemia, reperfusion lesions, peripheral vascular disease, pancreatitis, atherosclerosis, meningitis, vasculitis, dermatitis, myositis, renal inflammations, sepsis, septicemia (for example, endotoxemia), and septic strokes (for example, endotrophic stroke).

[0145] In another implementation, the invention also presents a method for treating tuberculosis in a

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animal (for example, a mammalian such as a human) comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the animal.

[0146] In another implementation, the invention also features the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for inhibiting an adenosine kinase in an animal (eg, a mammal such as a human).

[0147] In another implementation, the invention also presents the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a disease associated with the activity of adenosine kinases in an animal (for example, a mammal such as a human).

[0148] In another implementation, the invention also presents the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a disease associated with the activity of adenosine kinases in an animal (eg, a mammal such as a human).

Abbreviations

[0149]

AcOEt

Boc

bd

bs

Bu

Bz

calcd

cat.

d

dd

ddd

DMF

DMSO

dt

Et

EDTA

Fab

gem

HR

i

GO

m

m

I

MeOH

MeONa

MS

v

NMR

or

p

Ph

PPh3

Py

Pyrr

that

rel.

RT

s

sat.

Sun.

t

TBS

td

ADD-1

THF

TFA

TPPTS

ethyl acetate

tert-butoxycarbonyl

double wide

single broad

butyl

benzoyl

calculated

catalyst

doublet

double double

double doublet doublet

dimethylformamide

dimethylsulfoxide

triple doublet

ethyl

ethylenediaminetetracetic acid

fast atom bombardment geminal

high resolution ipso

infrared spectroscopy

multiplets

goal

methyl

methanol

sodium methoxide

mass spectrometna

wave number

nuclear magnetic resonance

ortho

for

phenyl

triphenylphosphine (triphenylphosphine)

pyridyl (pyridyl)

pyrrolyl (pyrrolyl)

quartet

relative

room temperature

individual

saturated

solution

triplet

tert-butyldimethylsilyl doublet triplet tris [2- (2-methoxyethoxy) ethyl] amine tetrahydrofuran trifluoroacetic acid

sodium triphenylphosphine trisulfonate (sodium triphenylphosphine trisulfonate)

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Tr trityl, triphenylmethyl

vic vicinal (vicinal)

[0150] The invention will now be illustrated by the following non-limiting examples. Examples

Example 1. 4-Ethyl-7- (pnD-ribofuranosyl) -7H-pyrrolo [2,3-d] pmmidma (3a)

[0151]

image16

[0152] Compound 2a (149 mg, 0.34 mM) is treated with 90% aqueous TFA (0.5 ml) for one hour at room temperature. The volatiles are removed to the ford and the residue is co-evaporated several times with MeOH. Chromatography on silica (3.5 percent n ^ l] 4% MeOH in CHCh) generates nucleoside 3a (100 mg, quantitative) as a colorless glassy solid. 1H NMR (600 MHz, DMSO-cfe): 1.30 (t, 3H, Jvic = 7.6, CH3CH2); 2.99 (q, 2H, Jvic = 7.6, CH2CH3); 3.54 (ddd, 1H, Jgem = 11.9, JSb, oH = 5.8, J & b, 4 '=

4.0, H-5'b); 3.63 (ddd, 1H, Jgem = 11.9, J? A, oH = 5.3, J & a, 4 '= 4.0, H-5'a); 3.91 (q, 1H, J4.5 = 4.0, J *, 3 '= 3.3, H-4'); 4.11 (td, 1H, J3 ', 2' = 5.1, J3, oh = 4.8, J3.4 = 3.3, H-3 '); 4.43 (td, 1H, J2, oh = 6.5, J2, r = 6.3, J2, s = 5.1, H-2 '); 5.13 (t, 1H, Joh, 5 = 5,8,5,3, OH-5 '); 5.19 (d, 1H, Joh, 3 = 4.8, OH-3 '); 5.35 (d, 1H, Joh, 2 '= 6.5, OH-2'); 6.18 (d, 1H, Jv, 2 = 6.3, H-1 '); 6.77 (dd, 1H, Ja, 6 = 3.7, J5.2 = 0.4, H-5); 7.78 (d, 1H, J6.5 = 3.7, H-6); 8.69 (s, 1 H, H-2). 13C NMR (151 MHz, DMSO-de): 12.93 (CH3CH2); 27.97 (CH2CH3); 61.87 (CH2-5 '); 70.87 (CH-3 '); 74.18 (CH-2 '); 85.38 (CH-4 '); 87.02 (CH-1 '); 100.09 (CH-5); 117.38 (C-4a); 126.78 (CH-6); 150.73 (C-7a); 151.15 (CH-2); 163.77 (C-4). MS FAB, m / z (rel.%): 149 (45), 280 (100) [M + H] .HR MS (FAB): calculated for C13H18N3O4 [M + H] 280,1297, found 280,1293.

[0153] Intermediate compound 2a is prepared as follows:

to. 4-EtM-7- {2,3-0-isopropylidene-5-0- (ferc-butyldimethylsMM) -p-D-ribofuransM} -7H-pyrrolo [2,3-

djpirimidine (2a). A mixture purged with argon of riboside protected from chlorodeazapurine 1 (200 mg, 0.454 mM), triethylaluminum

(1M sol in THF, 910 mL 0.91 mM) and Pd (PPh3) 4 (26 mg, 0.022 mM) in THF (5 mL) was stirred at 70 ° C for 20 hours. The mixture was diluted with hexane (30 ml) and washed with aqueous NH4Cl (sat., 10 mL), the aqueous phase was extracted again with hexane (2 X 10 ml). The collected organic extracts were dried over MgSO4, the volatiles were removed in vat and the residue was exposed to silica chromatography (hexanes-AcOEt, 10: 1 ^ D6: 1) generating the product 2a as a colorless oil (162 mg , 82%). 1H NMR (600 MHz, CDCh): 0.046 and 0.053 (2 xs, 2 x 3H, CH3SO; 0.90 (s, 9H, (CH3) BC); 1.39 (q, 3H, J = 0.6, (CH3) 2C); 1,393 (t, 3H, Jvic = 7.7, CH3CH2); 1.65 (q, 3H, J = 0.6, (CH3) 2C); 3.04 (q, 2H, Jvic = 7.7, CH2CH3); 3.79 (dd, 1H, Jgem = 11.2, J? B, 4 '= 4.0, H-5'b); 3.87 (dd, 1H, Jgem = 11.2, JSa, 4 '= 3.8, H-5'a); 4.33 (m, 1H, J4', 5 '= 4.0.3.8, J4', 3 '= 3, 1, J4 ', 2' = 0.4, H-4 '); 4.98 (ddd, 1H, Js, 2 = 6.3, JSa = 3.1, Js, v = 0.5, H- 3 '); 5.13 (ddd, 1H, J2', 3 '= 6.3, J2, r = 3.1, J2A = 0.4, H-2'); 6.41 (d, 1H, Jr, 2 = 3.1, H-1 '); 6.58 (d, 1H, J5S = 3.7, H-5); 7.43 (d, 1H, J6.5 = 3.7, H -6); 8.81 (s, 1H, H-2) .13C NMR (151 MHz, CDCh): - 5.50 and -5.40 (CHsSi); 12.87 (CH3CH2); 18.37 ( C (CH3) a); 25.47 ((CHa ^ C); 25.90 ((CHa) aC); 27.34 ((CHa) 2C); 28.61 (CH2CH3); 63.37 ((CH2 - 5 '); 80.94 (CH-3'); 84.80 (CH-2 '); 85.96 (CH-4'); 90.17 (CH-1 '); 100.09 (CH -5); 114.11 (C (CHs) 2); 117.70 (C-4a); 125.60 (CH-6); 150.39 (C-7a); 151.64 (CH-2) ; 164.25 (C-4).

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Example 2. 4-Benzyl-7- (B-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (3b).

[0154]

image17

[0155] Compound 2b (183 mg, 0.37 mM) is treated with 90% aqueous TFA (0.5 ml) for one hour at

room temperature The volatiles are removed in vacuo and the residue is sometimes evaporated with MeOH. Silicon chromatography (3% MeOH in CHCL) generates nucleoside 3b (107 mg, 85%) as a colorless glassy solid. 1H NMR (400 MHz, DMSO-cfe): 3.55 and 3.63 (2 X dd, 2H, Jgem = 11.9, J5’4 = 3.9, H-5 ’); 3.93 (q, 1H, J4 \ 5 ’= 3.9, J4 \ 3’ = 3.2, H-4 ’); 4.11 (dd, 1H, J3 \ 2 = 5.0, J3 «, 4« = 3.2, H-3 ’); 4.42 (dd, 1H, J2 \ r = 6.1, J2 \ 3 = 5.0, H-2 ’); 4.43 (s, 2H, CH2Ph); 4.7-5.3 (bs, 3H, OH-2 ’, 3’, 5 ’); 6.21 (d, 1H, Jr, 2 ’=

6.1, H-1 ’); 6.90 (d, 1H, J5.6 = 3.7, H-5); 7.22 (m, 1H, H-p-Ph); 7.29 (m, 2H, H-m-Ph); 7.38 (m, 2H, H-o-Ph); 7.94 (d, 1H, J6.5 = 3.7, H-6); 8.87 (s, 1H, H-2). 13C NMR (100.6 MHz, DMSO-d6): 39.91 (CH2Ph); 61.67 (CH2-5 ’); 70.78 (CH-3 ’); 74.32 (CH-2’); 85.60 (CH-4 ’); 87.11 (CH-1 ’); 101.30 (CH-5); 117.64 (C-4a); 126.92 (CH-p-Ph); 128.48 (CH-6); 128.76 (CH-m-Ph); 129.25 (CH-o-Ph); 137.66 (C - / - Ph); 149.22 (CH-2); 151.01 (C-7a); 159.30 (C-4). MS FAB, m / z (rel.%): 210 (100), 342 (85) [M + H]. HR MS (FAB): Calculated for Ci8H20N3O4 [M + H] 342.1454, found 342.1467.

[0156] Intermediate compound 2b is prepared as follows:

to. 4-Benzyl-7- {2,3-0-isopropylidene-5-0- (ferc-butyldimethylsilyl) -p-D-ribofuranosyl} -7H-pyrrolo [2,3-

c / Jpirimidine (2b). A mixture purged with argon of riboside protected from chlorodeazapurine 1 (191 mg, 0.43 mM), benzylzinc bromide (sol. 0.5M in THF, 1.75 ml, 0.875 mM) and Pd (PPh3) 4 (25mg , 0.022 mM) in THF (5 mL) is stirred at 70 ° C for 24 hours. The mixture is diluted with hexane (25 ml) and washed with aqueous NH4CI (sat., 10 ml), the aqueous phase is extracted again with hexane (2 X 10 ml). The collected organic extracts are dried over MgSO4, the volatiles are removed in vacuo and the residue is exposed to a silica chromatograph (hexanes-AcOEt, 6: 1) generating the product 2b in the form of a colorless oil (201 mg, 93% ). 1H NMR (400 MHz, CDCI3): 0.02 and 0.04 (2 X s, 2 X 3H, CH3Si); 0.88 (s, 9H, (CH3) 3C); 1.38 (q, 3H, J = 0.6, (CH3) 2C); 1.64 (q, 3H, J = 0.6, (CH3) 2C); 3.77 (dd, 1H, Jgem = 11.2, J5'b4 '= 4.0, H- 5'b); 3.86 (dd, 1 H, Jgem = 11.2, J5'a4' = 3.8, H-5'a); 4.31 (q, 1H, JA> 5> = 4.0, 3.8, J4 "3" = 3.1, H-4 '); 4.35 (s, 2H, CH2Ph); 4.96 (ddd, 1H, J3’2 ’= 6.3, J3“ 4- = 3.1, Jzv = 0.4, H-3 ”); 5.10 (dd, 1H, J2’3 ’= 6.3, J? V = 3.1, H-2’); 6.39 (d, 1 H, Jr2 = 3.1, H-1 ’); 6.43 (d, 1H, J56 = 3.7, H-5); 7.21 (m, 1H, H-p-Ph); 7.25-7.33 (m, 4H, H-o, m-Ph); 7.39 (d, 1 H, J65 = 3.7, H-6); 8.83 (s, 1H, H-2). i3C NMR (100.6 MHz, CDCI3): - 5.50 and -5.40 (CH3Si); 18.37 (C (CH3) 3); 25.47 ((CH3) 2C); 25.90 ((CH3) 3C); 27.34 ((CH3) 2C); 42.27 (CH2Ph); 63.38 (CH2-5 ’); 80.96 (CH-3 ’); 84.79 (CH-2 ’); 85.99 (CH-4 ’); 90.21 (CH-1 ’); 100.37 (CH-5); 114.15 (C (CH3) 2); 118.28 (C-4a); 126.00 (CH-6); 126.60 (CH-p-Ph); 128.57 and 129.07 (CH-o, m-Ph); 138.11 (C - / - Ph); 150.81 (C-7a); 151.65 (CH-

2); 161.14 (C-4). MS FAB, m / z (rel.%): 73 (100), 210 (30), 292 (10), 496 (95) [M + H]. HR MS (FAB): calcd for C27H38N304Si [M + H] 496.2632, found 496.2636.

Example 3. 4- (4-Methoxyphenyl) -7- (p-D-ribofuranosyl) -7H-pyrrolo [2,3-c /] pyrimidine (3d).

[0157]

image18

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[0158] Compound 2d (463 mg, 0.90 mM) is treated with 90% aqueous TFA (1 ml) at room temperature for one hour. The volatiles are removed to the ford and the residue is evaporated several times with MeOH. Silica chromatography (5% ^ 6% MeOh in cHcl3) generates the raw nucleoside 3d (405 mg, 125%), which was re-purified by reverse phase chromatography providing the desired product (200 mg, 62%) in the form of a colorless glassy solid. 1H NMR (500 MHz, DMSO-de): 3.57 and 3.66 (2 X dd, 2H, dgem = 11.9, JS4 '= 4.0, H-5'); 3.87 (s, 3H, CH3O); 3.94 (td, 1H, ^ 5 = 4.0, J * 3 '= 3.3, H-4'); 4.14 (dd, 1H, Ja2 = 5.1, Js # = 3.3, H-3 '); 4.46 (dd, 1H, J2r = 6.2, J2s = 5.1, H-2 '); 6.28 (d, 1H, Jr2 = 6.2, H-1 '); 7.03 (d, 1H, J56 = 3.8, H-5); 7.16 (m, 2H, H-m-C6H4OMe); 7.97 (d, 1H, J65 = 3.8, H-6); 8.17 (m, 2H, H-o-C6H4OMe); 8.86 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-de): 55.58 (CH3O); 61.73 (CH2-5 '); 70.77 (CH-3 '); 74.29 (CH-2 '); 85.42 (CH-4 '); 86.97 (CH-1 '); 101.43 (CH-5); 114.59 (CH-m-C6H4OMe); 114.94 (C-4a); 128.16 (CH-6); 129.38 (C - / - C6H4OMe); 150.59 (CH-2); 152.00 (C-7a); 155.47 (C-4); 161.39 (C-p-C6H4OMe). MS FAB, m / z (rel.%): 226 (100), 240 (30), 268 (20), 358 (15) [M + H]. HRMS (FAB): calculated for C18H20N3O5 [M + H] 358.1403, found 358.1414.

[0159] Intermediate 2d is prepared as follows:

to. 7- {2,3-0-IsopropiMdeno-5-0- (ferc-butNdimetNsiMl) -p-D-ribofurans} -4- (4-methoxyphene) -7H-

pyrrolo [2,3-d] pyrimidine (2d). A mixture purged with argon of chlorodeazapurine 1 ribosides (415 mg, 0.94 mM), 4-methoxyphenylboronic acid (215 mg, 1.41 mM), K2CO3 (195 mg, 1.4 mM) and Pd (PPh3) 4 (55 mg, 0.047 mM) in toluene (5 mL) was stirred at 100 ° C for 5 hours. The mixture was diluted with chloroform (20 ml) and washed with aqueous NH4Cl (sat., 20 mL), the aqueous phase was extracted again with chloroform (2 X 5 milliliters). The collected organic extracts are dried over MgSO4, the volatiles are removed in vat and the residue is exposed to a silica chromatography (hexanes-AcOEt, 7: 1) generating the product 2d in the form of a yellowish oil (482 mg, 100% ). 1H NMR (600 MHz, CDCl3): 0.06 and 0.07 (2 X s, 2X3H, CHaSi); 0.90 (s, 9H, (CH3) 3C); 1.40 and 1.67 (2 X q, 2 X 3H, J = 0.6, (CHs ^ C); 3.81 (dd, 1H, Jgem = 11.1, J5'b4 '= 3.9 , H-5'b); 3.90 (dd, 1H, Jgem = 11.1, Jsa4 '= 3.8, H-5'a); 3.90 (s, 3H, CH3O); 4.35 (ddd, 1H, J45 '= 3.9,

3.8, J4 '3' = 3.2, H-4 '); 5.00 (ddd, 1H, JS2 = 6.3, Js * = 3.2, Jsr = 0.4, H-3'); 5.15 (dd, 1H, J2S = 6.3, J2r = 3.0, H-2 '); 6.48 (d, 1H, Jr2 = 3.0, H-1'); 6.83 (d, 1H, J56 = 3.8, H-5); 7.07 (m, 2H, H-m-C6H4OMe); 7.53 (d, 1H, J65 =

3.8, H-6); 8.09 (m, 2H, Ho-C6H4OMe); 8.93 (s, 1 H, H-2). 13C NMR (151 MHz, CDCls): -5.48 and -5.37 (CH3Si); 18.39 (C (CH3) 3); 25.49 ((CH3) 2C); 25.92 ((CHsfeC); 27.36 ((CHs ^ C); 55.40 (CH3O); 63.39 (CH2-5 '); 80.93 (CH-3'); 84.93 (CH -2 '); 86.03 (CH-4'); 90.22 (CH-1 '); 101.51 (CH-5); 114.13 (C (CH3) 2); 114.18 (CH -m- C6H4OMe); 115.85 (C-4a); 126.38 (CH-6); 130.32 (CH-o-C6H4OMe); 130.65 (C - / - C6H4OMe); 151.59 ( C-7a); 151.66 (CH-2); 157.21 (C-4); 161.23 (Cp-C6 ^ OMe). MS FAB, m / z (rel.%): 73 (100) , 226 (25), 512 (45) [M + H] HRMS (FAB): Calculated for C27H3aN3O5Si [M + H] 512.2581, found 512.2575.

Example 4. 4- (4-Fluorophenyl) -7- (P-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (3e).

[0160]

image19

[0161] Compound 2e (328 mg, 0.66 mM) is treated with 90% aqueous TFA (0.5 ml) for one hour at room temperature. The volatiles are removed to the ford and the residue is co-evaporated several times with MeOH. Silica chromatography (5% ^ 6% MeOH in CHCl3) generates nucleoside 3e (214 mg, 94%) as a white solid. The compound is crystallized from MeOH / chloroform. H NMR (500 MHz, DMsO-de): 3.57 (ddd, 1H, Jgem = 11.9, J5bOH = 5.6, JSb4 '= 4.0, H-5'b); 3.66 (ddd, 1H, Jgem = 11.9, J5'a oh = 5.4, J & b4 '= 4.0, H-5'a); 3.95 (td, 1H, J4'5 '= 4.0, J4'3 = 3.3, H-4'); 4.14 (ddd, 1H, JS2 = 5.1, JSoh = 4.9, J34 = 3.3, H-3 '); 4.46 (ddd, 1H, J2 OH = 6.4, J2r = 6.2, J23-5.1, H-2 '); 5.09 (dd, 1H, Joh5 '= 5.6, 5.4, OH-5'); 5.19 (d, 1H, J oh3 '= 4.9, OH-3'); 5.39 (d, 1H, Joh2 '= 6.3, OH-2'); 6.29 (d, 1H, Jr2 = 6.2, H-1 '); 7.02 (d, 1H, J56 = 3.8, H-5); 7.43 (m, 2H, H-m-C6H4F); 7.98 (d, 1H, J65 = 3.8, H-6); 8.25 (m, 2H, H-0-C6H4F); 8.89 (s, 1 H, H-2). 13C NMR (125.7 MHz, DMSO- de): 61.73 (CH2-5 '); 70.76 (CH-3 '); 74.25 (CH-2 '); 85.39 (CH-4 '); 86.92 (CH-1 '); 100.98 (CH-5); 115.38 (C-4a); 116.09 (d, Jc, f = 22, CH-m-C6H4F); 128.33 (CH-6); 131.13 (d, Jc, f = 9, CH-0-C6H4F); 134.15 (d, Jc, f = 3, C - / -

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C6H4F); 151.13 (CH-2); 152.17 (C-7a); 155.10 (C-4); 163.55 (d, Jcf = 248, C-P-C6H4F). 19F NMR (470.3 MHz, DMSO-d6): - 111.14. IR (KBr): v = 1627, 1606, 1568, 1515, 1460, 1357, 1235, 1098, 1049 cm-1. MS FAB, m / z (rel.%): 214 (100), 346 (35) [M + H]. HR MS (FAB): Calculated for C17H17FN3O4 [M + H] 346,1203, found 346.1212.

[0162] Intermediate compound 2e is prepared as follows:

а. 4- (4-Fluorofeml) -7- {2,3-O-isopropylidene-5-0- (ferc-butyldimethylsilyl) -p-D-ribofuranosyl} -7H- pyrrolo [2,3-d] pyrimidine (2e). A mixture purged with argon of chlorodeazapurine 1 ribosides (409 mg, 0.93 mM), 4-fluorophenylboronic acid (195 mg, 1.39 mM), K2CO3 (192 mg, 1.39 mM) and Pd (PPh3) 4 (54 mg, 0.047 mM) in toluene (5 mL) is stirred at 100 ° C for 5 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous NH4Cl (sat., 20 mL), the aqueous phase is reextracted with chloroform (2 X 5 milliliters). The collected organic extracts are dried over MgSO4, the volatiles are removed to the ford and the residue is exposed to silica chromatography (hexanes-AcOEt, 10: 1 -D7: 1) generating the product 2e in the form of a colorless oil (356 mg , 77%). 1H NMR (600 MHz, CDCh): 0.07 and 0.08 (2Xs, 2X3H, CH3Si); 0.91 (s, 9H, (CH3) 3C); 1.41 (q, 3H, J = 0.7, (CH3) 2C); 1.67 (q, 3H, J = 0.7, (CH3) 2C); 3.82 (dd, 1H, Jgem = 11.3, J5'b4 '= 3.8, H-5'b); 3.91 (dd, 1H, Jgem = 11.3, JSa4 = 3.6, H-5'a); 4.37 (q, 1H, J4'5 = 3.8,3.6, J4'3 = 3.1, H-4 '); 5.00 (ddd, 1H, J32' = 6.2, J34 '= 3.1, J31' = 0.4, H-3 '); 5.13 (dd, 1H, J2s =

б, 2, J2r = 3.1, H-2 '); 6.50 (d, 1H, Jrz = 3.1, H-1'); 6.80 (d, 1H, J56 = 3.7, H-5); 7.25 (m, 2H, H-m-C6H4F); 7.59 (d, 1H, J65 = 3.7, H-6); 8.11 (m, 2H, H-o-C6H4F); 8.96 (s, 1H, H-2). 13C NMR (151 MHz, CDCh): -5.51 and -5.38 (CH3Si); 18.38 (C (CH3) 3); 25.45 ((CH3) 2C); 25.89 ((CH3) 3C); 27.35 ((CH3) 2C); 63.38 (CH2-5 '); 80.85 (CH-3 '); 84.96 (CH-2 '); 85.95 (CH-4 '); 90.18 (CH-1 '); 101.15 (CH-5); 114.16 (C (CH3) 2); 115.85 (d, Jc, f = 22, CH-m-C6H4F); 116.11 (C-4a); 126.84 (CH-6); 130.73 (d, Jcf = 9, CH0-C6H4F); 134.17 (d, Jcf = 3, C-i-C6H4F); 151.60 (C-7a); 151.63 (CH-2); 156.42 (C-4); 163.93 (d, Jcf = 250, CP-C6H4F). 19F NMR (470.3 MHz, CDCl3): - 111.16. MS FAB, m / z (rel.%): 73 (100), 214 (20), 500 (30) [M + H]. HR MS (FAB): calculated for C26H35FN3O4Si [M + H] 500.2381, found 500.2366.

Example 5. 4- (Furan-2-yl) -7- (P-D-ribofuranosyl) -7H-pyrrolo [2,3-c /] pyrimidine (3f)

[0163]

image20

[0164] Compound 2f (276 mg, 0.58 mM) is treated with 90% aqueous TFA (0.5 ml) for one hour at room temperature. The volatiles are removed to the ford and the residue is co-evaporated several times with MeOH. The compound is crystallized from MeOH / AcOEt generating the product 3f as a beige powder (117 mg, 63%). 1H NMR (400 MHz, DMSO-cfe): 3.57 and 3.66 (2 X dd, 2H, Jgem = 11.9, Js # = 4.0, H-5 '); 3.94 (q, 1H, J4'5 '= 4.0, J4'3' = 3.3, H-4 '); 4.13 (dd, 1H, J22 = 5.1, JS4 = 3.3, H-3 '); 4.45 (dd, 1H, J2r = 6.2, J2S = 5.1, H-2 '); 6.25 (d, 1H, Jr2 '= 6.2, H-1'); 6.80 (dd, 1H, J43 = 3.5, J45 = 1.7, H-4-furyl); 7.08 (d, 1H, J56 = 3.7, H-5); 7.50 (dd, 1H, J34 = 3.5, J35 = 0.7, H-3-furyl); 7.95 (d, 1H, J65 = 3.7, H-6); 8.07 (dd, 1H, J54 = 1.7, J53 = 0.7, H-5-furyl); 8.78 (s, 1H, H-2). 13C NMR (100.6 MHz, DMSO-de): 61.74 ((CH2-5 '); 70.76 (CH-3'); 74.24 (CH-2 '); 85.40 (CH- 4 '); 86.88 (CH-1'); 101.41 (CH-5); 112.79 (C-4a); 112.89 (CH-4-furyl); 113.62 (CH-3 -furyl); 128.32 (CH-6); 146.36 (C-4); 146.60 (CH-5-furyl); 151.00 (CH-2); 152.24 (C-7a) ; 152.43 (C-2-furyl). IR (KBr): v = 1675, 1601, 1564, 1462, 1353, 1237, 1207, 1188, 1099, 1051, 1016 cm'1. MS FAB, m / z (rel.%): 186 (100), 318 (10) [M + H] HR MS (FAB): calculated for C17H17N3O4 [M + H] 318,1090, found 318,1089.

[0165] Intermediate compound 2f is prepared as follows:

F. 4- (Furan-2-yl) -7- {2,3-O-isopropylidene-5-O- (ferc-butyldimethylsilyl) -p-D-ribofuranosyl} -7H-pyrrolo [2,3-djpyrimidine (2f). A mixture purged with argon of chlorodeazapurine 1 ribosides (294 mg, 0.67 mM), 2- (tributyl stenyl) furan (252 mL, 0.80 mM) and PdCl2 (PPh3) 2 (24 mg, 0.03 mM) in DMF (3 mL) it is stirred at 100 ° C for 2 hours. The volatiles are removed to the ford and the residue is co-evaporated several times with toluene. Silica column chromatography (hexanes-AcOEt, 20: 1 -10: 1) generates the product 2f in the form of a colorless foam (2.93 milligrams, 93%), 1H NMR (600 MHz, CDCh): 0.069 and 0.074 (2 X s, 2 X

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3H, CHaSi); 0.91 (s, 9H, (CHs ^ C); 1.40 and 1.67 (2 X q, 2 X 3H, J = 0.6,

(CHa) 2C); 3.81 (dd, 1H, Jgem = 11.2, J? 6.4 '= 3.7, H-5'b); 3.90 (dd, 1H, Jgem = 11.2, JSa, 4 '= 3.5, H-5'a); 4.36 (ddd, 1H, J4'5 '= 3.7, 3.5, Jra = 3.1, H-4'); 4.99 (ddd, 1H, Jaz = 6.3, Ja4 '= 3.1, Jar = 0.4, H-3'); 5.12 (dd, 1H, Jza = 6.3, Jzr = 3.1, H-2 '); 6.47 (d, 1H, Jrz = 3.1, H-1 '); 6.64 (dd, 1H, J43 = 3.5, J45 = 1.7, H-4-furyl); 7.05 (d, 1H, J5 6 = 3.7, H-5); 7.41 (dd, 1H, J34 = 3.5, J35 = 0.8, H-3-furyl); 7.56 (d, 1H, J65 = 3.7, H-6); 7.72 (dd, 1H, J54 = 1.7, J53 = 0.8, H-5-furyl); 8.87 (s, 1H, H-2). 13C NMR (151 MHz, CDCh): -5.50 and -5.38 (CHsSi); 18.38 (C (CH3) 3); 25.45 ((CHs) 2C); 25.90 ((CHs ^ C); 27.33 ((CHs ^ C); 63.36 (CH2-5 '); 80.85 (CH-3'); 84.92 (CH-2 '); 85.94 (CH-4 '); 90.04 (CH-1'); 102.11 (CH-5); 112.36 (CH-4-furyl); 112.97 (CH-3-furyl) ; 113.55 (C-4a); 114.13 (C (CHs) 2); 126.80 (CH-6); 145.11 (CH-5-furyl); 147.12 (C-4); 151.41 (CH-2); 151.82 (C-7a); 152.95 (C-2- furyl.) MS FAB, m / z (rel.%): 73 (100), 186 (20) , 472 (45) [M + H] HR MS (FAB): calculated for C24H34NsO5Si [M + H] 472.2268, found 472.2274.

Example 6. 7- (p-D-RibofuranosM) -4- (thiophen-2-yl) -7H-pyrrolo [2,3-c /] pyrimidma (3g).

[0166]

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[0167] Compound 2g (200 mg, 0.41 mM) is treated with 90% aqueous TFA (0.5 milliliters) for one hour at room temperature. The volatiles are removed to the ford and the residue is co-evaporated several times with MeOH. The residue is crystallized from MeOH / AcOEt generating the product 3g in the form of a yellow powder (85 mg, 62%) a reverse phase chromatography of mother liquors provided an additional 36 mg (26%) of the product. The total generation of the 3g product is therefore 88%. 1H NMR (400 MHz, DMSO-cfe): 3.57 and 3.66 (2 X dd, 2H, Jgem = 11.9, Ja4 '= 4.0, H-5'); 3.94 (q, 1H, Jra = 4.0, Jra = 3.4, H-4 '); 4.14 (dd, 1H, Jaz =

5.0, Ja, 4 = 3.4, H-3 '); 4.45 (dd, 1H, J2, r = 6.1, Jz, a = 5.0, H-2 '); 6.25 (d, 1H, Jr, z = 6.1, H-1 '); 7.18 (d, 1H, Ja, 6 = 3.8, H-5); 7.31 (dd, 1H, J45 = 5.1, J43 = 3.8, H-4-thienyl); 7.86 (dd, 1H, J54 = 5.1, J53 = 1.0, H-5-thienyl); 7.97 (d, 1H, J65 = 3.8, H-6); 8.18 (dd, 1H, J34 = 3.8, J35 = 1.0, H-3-thienyl); 8.75 (s, 1H, H-2). 13C NMR (100.6 MHz, DMSO- de): 61.70 (CH2-5 '); 70.72 (CH-3 '); 74.26 (CH-2 '); 85.36 (CH-4 '); 86.95 (CH-1 '); 100.95 (CH-5); 113.12 (C-4a); 128.40 (CH-6); 129.23 (CH-4-thienyl); 129.72 (CH-3-thienyl); 130.88 (CH-5-thienyl); 142.56 (C-2-thienyl); 150.23 (C-4); 150.91 (CH-2); 152.18 (C-7a). IR (KBr): v = 1628, 1569, 1513, 1451, 1414, 1355, 1099, 1051 cm'1. MS FAB, m / z (rel.%): 202 (45), 334 (100) [M + H]. HR MS (FAB): calculated for C15H16N3O4S [M + H] 334.0862, found 334.0869.

[0168] Intermediate 2g is prepared as follows:

to. 7- {2,3-0-IsopropiMdene-5-0- (ferc-butMdimetMsilM) -p-D-ribofuranosyl} -4- (thiophene-2-yl) -7H-

pyrrolo [2,3-d] pyrimidma (2g). A mixture purged with argon of chlorodeazapurine 1 ribosides (208 mg, 0.47 mM), 2- (tributilestanyl) thiophene (165 mL, 0.52 mM) and PdCl2 (PPhs) 2 (17 mg, 0.02 mM) in DMF (2 mL) it was stirred at 100 ° C for 2 hours. The volatiles were removed in vat and the residue was evaporated several times in toluene. Silica column chromatography (hexanes-AcOEt, 50: 1 -15: 1) generates the product 2g in the form of a colorless foam (219 mg, 95%). 1H NMR (600 MHz, CDCls): 0.070 and 0.074 (2 X s, 2 X 3H, CHsSi); 0.91 (s, 9H, (CHs ^ C); 1.40 and 1.67 (2 X q, 2 X 3H, J = 0.6, (CHs) 2C); 3.82 (dd, 1H, Jgem = 11.2, JaM '= 3.8, H-5'b); 3.91 (dd, 1H, Jgem = 11.2, JSa, 4' = 3.6, H-5'a); 4.36 (ddd, 1H, J4 5 '= 3.8, 3.6, J43 = 3.1, H-4'); 4.99 (ddd, 1H, Jaz = 6.3, Jar = 3, 1, Jar = 0.4, H-3 '); 5.13 (dd, 1H, Jza = 6.3, Jzr = 3.0, H-2'); 6.47 (d, 1H, Jrz = 3.0, H-1 '); 6.91 (d, 1H, J56 = 3.8, H-5); 7.24 (dd, 1H, J45 = 5.0, J43 = 3.8, H -4-thienyl); 7.57 (dd, 1H, J54 = 5.0, J53 = 1.1, H-5-thienyl); 7.59 (d, 1H, J65 = 3.8, H- 6 ); 7.97 (dd, '1H, J34 = 3.8, J35 = 1.1, H-3-thienyl); 8.87 (s, 1H, H-2). 13C NMR (151 MHz, CDCh ): -5.50 and -5.37 (CHsSi); 18.38 (C (CHs) 3); 25.45 ((CHs ^ C); 25.90 ((CHs ^ C); 27.34 ( (CHs ^ C); 63.37 (CH2-5 '); 80.87 (CH-3'); 84.98 (CH-2 '); 86.05 (CH-4');

90.24 (CH-1 '); 101.02 (CH-5); 114.00 (C-4a); 114.13 (C (CHs) 2); 126.92 (CH-6); 128.36 (CH-4-thienyl); 128.72 (CH-3-thienyl); 129.56 (CH-5-thienyl); 142.77 (C-2-thienyl); 151.04 (C-4); 151.40 (CH-2); 151.70 (C-7a). MS FAB, m / z (rel.%): 73 (100), 202 (25), 488 (43) [M + H]. HR MS (FAB): calculated for C24H34N3O4SSi [M + H] 488,2039, found 488,2032.

Example 7. 4- (1H-Pyrrol-2-yl) -7- (P-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (3h).

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[0170] Compound 2h (385 mg, 0.67 mM) is treated with 90% aqueous TFA (0.5 ml) for one hour at room temperature. The volatiles are removed to the ford and the residue is co-evaporated several times with MeOH. The residue crystallizes after the addition of a little MeOH generating 3h in the form of yellow crystals (67 mg, 31%) to the product, reverse phase chromatography of the mother liquors facilitates the additional 3h product (112 mg, 52%) . The total production is 83%. 1H NMR (500 MHz, DMSO-de): 3.57 (ddd, 1H, Jgem = 11.8, J5bOH = 5.6, JSb4 '= 4.0, H-5’b); 3.66 (ddd, 1H, Jgem = 11.8, J5’aOH = 5.0, J5a4 = 4.2, H-5’a); 3.93 (ddd, 1H, J4’5 ’= 4.2, 4.0, J4’ 3 ’= 3.0, H-4’); 4.13 (bddd, 1H, JS2 = 4.0, J3oh = 3.7, Js # = 3.0, H-3 ’); 4.45 (bddd, 1H, J2r =

6.1, Jzoh = 4.9, J2’3 ’= 4.0, H-2’); 5.12 (dd, 1H, Joh5 ’= 5.6, 5.0, OH-5’); 5.16 (bd, 1H, Joh3 ’= 3.7, OH-3’); 5.35 (bd, 1H, Joh2 ’= 4.9, OH-2’); 6.21 (d, 1H, Jr2 = 6.1, H-1 ’); 6.30 (dt, 1H, J43 = 3.8, J45 = J4nh = 2,4, H-4-pyrr); 7.037 (d, 1H, J5.6 = 3.8, H-5); 7.041 (ddd, 1H, J5, nh = 2.8, J5A = 2.4, J5.3 = 1.3, H-5-pyrr); 7.18 (ddd, 1H, J3A = 3.8, J3nh = 2.5, J3 5 = JhF = 1.3, H-3-pyrr); 7.82 (d, 1H, J65 = 3.8, H-6); 8.68 (s, 1 H, H-2); 11.80 (bs, 1H, NH). 13C NMR (125.7MHz, DMSO-d6): 61.82 (CH2-5 ’); 70.79 (CH-3 ’); 74.15 (CH-2 ’); 85.30 (CH-4 ’); 87.01 (CH-1 ’); 101.04 (CH-5); 112.13 (C-4a); 112.19 (CH-4-pyrr); 113.20 (CH-3-pyrr); 122.86 (CH-5-pyrr); 127.02 (CH-6); 129.11 (C-2-pyrr); 148.99 (C-4); 150.85 (CH-2); 151.66 (C-7a). IR (KBr): v = 1578, 1560, 1515, 1458, 1271, 1132, 1110, 1058, 1017 cm'1. MS FAB, m / z (rel.%): 317 (100) [M + H] .HRMS (FAB): calculated for C15H17N4O4 [M + H] 317.1250, found 317.1248. Anal. calculated for C15H16N4O4: C, 56.96; H, 5.10; N, 17.71. Found: C, 56.54; H, 5.10; N 17.60.

[0171] Intermediate 2h is prepared as follows:

to. 4- {1- (ferc-Butoxicarboml) -1H-pyrrole-2-M) -7- {2,3-0-isopropylidene-5-0- (ferc-

butMdimetMsilil) -p-D-ribofuranosyl} -7H-pyrrolo [2,3-d] pyrimidma (2h). A mixture purged with argon of chlorodeazapurine 1 ribosides (403 mg, 0.92 mM), 1-W- (Boc) -pyrrol-2-boronic acid (289 mg, 1.37 mM), K2CO3 (253 mg, 1 , 83 mM) and Pd (PPh3) 4 (53 mg,

0.05 mM) in dimethoxyethane (4 mL) / H2O (1 mL) is stirred 100 ° C for 4 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous NH4Cl (sat., 20 mL), the aqueous phase is extracted again with chloroform (2 X 5 milliliters). The organic extracts collected are dried over MgSO4, the volatiles are removed to the ford and the residue is exposed to silica chromatography (hexanes-AcOEt, 18: 1 -17: 1) generating the product 2h in the form of a reddish foam (397 mg, 76%). 1H NMR (500 MHz, CDCh): 0.057 and 0.063 (2 X s, 2 X 3H, CH3SO; 0.90 (s, 9H, (CH3) 3CSi); 1.28 (s, 9H, (CH3) 3CO) ; 1.40 and 1.66 (2 X q, 2 X 3H, J = 0.6, (CH3) 2C); 3.79 (dd, 1H, Jgem = 11.2, J & b, 4 '= 3, 9, H-5'b); 3.89 (dd, 1H, Jgem = 11.2,

J5’a, 4 ’

= 3.9, H-5’a); 4.33 (td, 1H, J4 5 ’= 3.9, J4 3’ = 3.2, H-4 ’); 4.99 (ddd, 1H, J3 2 = 6.5, J3 ’4’ = 3.2, J3 ’1’ = 0.4, H-3 ’); 5.13 (dd, 1H, J23 = 6.5, J2v = 2.9, H-2 ’); 6.33 (dd, 1H, J43 = 3.4, J45 = 3.2, H-4-pyrrole); 6.44 (d, 1H, Jr2 ’= 2.9, H-1’); 6.56 (d, 1H, J56 = 3.8, H-5); 6.67 (dd, 1H, J34 = 3.4, J35 = 1.7, H-3-pyrrole); 7.46 (dd, 1H, J54 = 3.2, J53 = 1.7, H-5-pyrrole); 7.49 (d, 1H, J65 = 3.8, H-6); 8.88 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): -5.47 and -5.37 (CH3Si); 18.38 (SiC (CH3) 3); 25.51 ((O-hhC); 25.91 ((CH3) 3CSi); 27.37 ((CH3) 2C); 27.41 ((CH3) 3CO); 63.37 (CH2-5 '); 80.94 (CH-3 '); 84.07 (OC (CH3) 3); 84.95 (CH-2'); 86.01 (CH-4 '); 90.23 (CH-1') ; 101.25 (CH-5); 110.94 (CH-4-pyrrole); 114.15 (C (CH3) 2); 117.35 (C-4a); 117.80 (CH-3-pyrrole ); 124.98 (CH-5-pyrrole); 126.39 (CH-6); 130.83 (C-2-pyrrole); 149.07 (CO); 150.93 (C-7a); 151 , 16 (CH-2); 152.05 (C-4). MS FAB, m / z (rel.%): 73 (100), 471 (15), 515 (25), 571 (30) [M + H] HR MS (FAB): calculated for C2gH43N4O6Si [M + H] 571.2952, found 571.2957.

Example 8. 7- (P-D-Ribofuranosil) -4- (thiazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidma (3i).

[0172]

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[0173] Compound 2i (459 mg, 0.94 mM) is treated with 90% aqueous TFA (1 ml) for one hour at room temperature. Volatiles are removed in vacuo and the residue is co-evaporated several times with MeOH. Silica chromatography (4% MeOH in CHCL) generates nucleiide 3i (268 mg, 85%) as a yellow solid. The compound crystallizes from MeOH. 1H NMR (600 MHz, DMSO-cfe): 3.58 (ddd, 1H, Jgem = 11.9, J5’bOH = 5.6, J5’b4 ’= 3.9, H-5’b); 3.66 (ddd, 1H, Jgem = 11.9, J5aoH = 5.3, J5’a4 ’= 3.9, H-5’a); 3.96 (td, 1H, J4’5 ’= 3.9 J4’3’ = 3.3, H-4 ’); 4.14 (ddd, 1H, J22 = 5.0, J3 0h = 4.8, J3 "4- = 3.3, H-3"); 4.46 (ddd, 1H, J? Oh = 6.3, J? R = 6.2, J2’3 ’= 5.0, H-2’); 5.12 (dd, 1H, J0H5 ’= 5.6, 5.3, OH-5’); 5.24 (d, 1H, J0H3 = 4.8, OH-3 ’); 5.44 (d, 1H, J0H2 ’= 6.3, OH-5’); 6.28 (d, 1H, JV2 = 6.2, H-1 ’); 7.30 (dd, 1H, J56 = 3.7, J52 = 0.4, H-5); 8.03 (d, 1 H, J6.5 = 3.7, H-6); 8.05 (d, 1H, J5.4 = 3.1, H-5-thiazolyl); 8.21 (d, 1H, J4.5 = 3.1, H-4-thiazolyl); 8.88 (s, 1H, H-2). 13CNMR (151MHz, DMSO-c / e): 61.80 (CH2-5 ’); 70.87 (CH-3 ’); 74.43 (CH-2 ’); 85.56 (CH-4 ’); 86.94 (CH-1 ’); 102.21 (CH-5); 113.87 (C-4a); 124.27 (CH-5-thiazolyl); 129.82 (CH-6); 145.80 (CH-4-thiazolyl); 148.24 (C-4); 151.10 (CH-2); 152.92 (C-7a); 167.50 (C-2-thiazolyl). IR (KBr): v = 1631, 1574, 1510, 1453, 1403, 1121, 1088, 1034 cm'1. MS FAB, mlz (rel.%): 203 (70), 335 (100) [M + H]. HR MS (FAB): Calculated for C14H15N4O4S [M + H] 335.0814, found 335.0824.

[0174] Intermediate compound 2i is prepared as follows:

а. 7- {2,3-0-lsopropylidene-5-0- (ferc-butyldimethylsilyl) -pD-ribofuranosyl} -4- (thiazol-2-yl) -7H- pyrrolo [2,3-c /] pyrimidine (2i ). A mixture purged with argon of chlorodeazapurine 1 ribosides (455 mg, 1.03 mM), 2- (tributilestanil) thiazole (611 mg, 1.63 mM) and PdCI2 (PPh3) 2 (36 mg, 0.05 mM) in DMF (3 mL) it is stirred at 100 ° C for 16 hours. The volatiles are removed in vacuo and the residue is co-evaporated several times with toluene. Silica column chromatography (hexanes-AcOEt, 30: 1 -> 20: 1) generates the product 2i in the form of a colorless oil (454 mg, 90%). 1H NMR (600 MHz, CDCI3): 0.07 and 0.08 (2 X s, 2 X 3H, CH3Si); 0.91 (s, 9H, (CH3) 3C); 1.40 and 1.67 (2 X q, 2 X 3H, J = 0.5, (CH3) 2C); 3.82 (dd, 1H, Jgem = 11.2, J5'b, 4 '= 3 , 8, H-5'b); 3.90 (dd, 1H, Jgem = 11.2, J5a, 4- = 3.6, H-5’a); 4.36 (ddd, 1H, J4 ’5 = 3.8, 3.6, J4“ 3 ”= 3.0, H-4’); 4.99 (dd, 1H, J22 = 6.4, J3> 4> = 3.0, H-3 ’); 5.11 (dd, 1H, J23 ’=

б, 4 J2, v = 3.1, H-2 ’); 6.50 (d, 1H, Jv, 2 = 3.1, H-1 ’); 7.41 (d, 1H, J5.6 = 3.7, H-5); 7.31 (d, 1H, J5.4 = 3.1, H-5- thiazolyl); 7.66 (d, 1H, J65 = 3.7, H-6); 8.10 (d, 1H, J45 = 3.1, H-4-thiazolyl); 8.92 (s, 1 H, H-2). 13C NMR (151 MHz, CDCI3): -5.49 and -5.37 (CH3Si); 18.39 (C (CH3) 3); 25.47 ((CH3) 2C); 25.92 ((CH3) 3C); 27.36 ((CH3) 2C); 63.40 (CH2-5 ’); 80.89 (CH-3 ’); 85.04 (CH-2 ’); 86.04 (CH-4’); 90.14 (CH-1 ’); 102.91 (CH-5); 114.17 (C (CH3) 2); 114.69 (C-4a); 122.27 (CH-5-thiazolyl); 128.28 (CH-6); 145.11 (CH-4-thiazolyl); 148.89 (C-4); 151.18 (CH-2); 152.45 (C-7a); 168.05 (C-2-thiazolyl) .MSFAB, m / z (rel.%): 73 (100), 203 (45), 489 (80) [M + H]. HR MS (FAB): Calculated for C23H33N404SSi [M + H] 489.1992, found 489.1974.

Example 9. 4- (1H-lmidazol-4-yl) -7- (p-D-ribofuranosyl) -7H-pyrrolo [2,3-c /] pyrimidine (3j).

[0175]

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[0176] Compound 2j (448 mg, 0.63 mM) is treated with 90% aqueous TFA (1 ml) for 18 hours at

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room temperature The volatiles are removed to the ford and the residue is co-evaporated several times with MeOH. Silica column chromatography (1.7% ^ H2% NH3 aq. [25%], 9% ^^ 12% MeOH in CHCb) generated nucleoside 3j (185 mg, 93%) as a white solid which is difficult to solubilize. The compound crystallizes from water. 1H nMr (600 MHz, DMSO-cfe): 3.56 (ddd, 1H, Jgem = 11.8, J5bOH = 5.5, Jsb4 = 4.1, H- 5'b); 3.65 (ddd, 1H, Jgem = 11.8, JSaOH = 5.5, J & a4 '= 3.5, H-5'a); 3.93 (ddd, 1H, JAS = 4.1, 3.5, J4 3- 3.4, H-4 ');

4.12 (ddd, 1H, J3, z = 5.3, J3, oh = 4.4, 'J3.4 = 3.4, H-3'); 4.45 (ddd, 1H, J2, r = 6.2, J2, oh = 5.9, J2.3 '= 5.3, H-2'); 5.13 (t, 1H, Joh5 = 5.5, OH-5 '); 5.18 (d, 1 H, Joh3 '= 4.4, OH-3'); 5.37 (d, 1H, Joh2 '= 5.9, OH-2'); 6.22 (d, 1H, Jr2 = 6.2, H-1 '); 7.33 (d, 1H, J56 = 3.0, H-5); 7.77 (d, 1H, J65 = 3.0, H-6); 7.91 (bs, 1H, H-2-imidazole); 8.03 (bs, 1H, H-5- imidazole); 8.68 (s, 1 H, H-2); 12.60 (bs, 1H, NH). 13C NMR (151 MHz, DMSO-de): 61.88 (CH2-5 '); 70.87 (CH-3 '); 74.15 (CH-2 '); 85.31 (CH-4'); 86.86 (CH-1 '); 103.05 (CH-5); 113.88 (C-4a); 119.09 (CH-5-imidazole); 126.68 (CH-6); 137.37 (CH-2-imidazole); 140.45 (C-4-imidazole); 151.06 (CH-2); 152.14 and 152.19 (C-4.7a). IR (KBr): v = 1593, 1569,1455,1396,1251, 1191, 1102, 1064, 1036 cm'1. MS FAB, m / z (rel.%): 318 (100) [M + H]. HR MS (FAB): Calculated for C14H16NsO4 [M + H] 318.1202, found 318.1191. Calculated for C14H15N504 0.35H2O: C, 51.96; H, 4.89; N, 21.64. Found: C, 51.74; H, 4.60; N, 21.78.

[0177] Intermediate compound 2j is prepared as follows:

to. 7- {2,3-0-Isopropylidene-5-0- (ferc-butyldimethylsilyl) -p-D-ribofuranosyl} -4- (1-trityl-1H-

imidazol-4-yl) -7H-pyrrolo [2,3-d] pyrimidine (2j). Ethylmagnesium bromide (1M solution in THF, 2.3 ml, 2.3 mM) is added to a solution purged with argon of 4-iodo-1-trityl-1H-imidazole (872 mg, 2 mM) in dry THF (6 ml) and the resulting solution is stirred for 10 minutes at room temperature, followed by the addition of the ZnCh solution (1M sol. In THF, 4 mL, 4mM). The mixture is stirred for 2 hours at room temperature and the resulting white thick mixture is transferred to an argon purged flask with chlorodeazapurine 1 (440 mg, 1 mM) and Pd (PPh3) 4 (58 mg, 0.05 mM ) and stir at 95 ° C for 12 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous EDTA (sat., 20 mL). The aqueous layer is extracted again with chloroform (2 X 5 milliliters). The organic extracts collected are dried over MgSO4, evaporated and exposed to silica chromatography (hexanes, AcOEt, 2.5: 1) generating the product 2j (474 mg, 66%) in the form of a reddish foam. H NMR (500 MHz, CDCb): 0.053 and 0.056 (2 X s, 2 X 3H, CH3SO; 0.90 (s, 9H, (CH3) 3CSi); 1.39 and 1.66 (2 X bs, 2 X 3H, (CH3) 2C); 3.79 (dd, 1H, Jgem = 11.1, Jsb4 '= 3.9, H-5'b); 3.87 (dd, 1H, Jgem = 11.1 , J5'4 '= 3.9, H-5'a); 4.32 (td, 1H, J4 5' = 3.9, J4'3 = 3.2, H-4 '); 4.99 (dd, 1H, J32 '= 6.4, J34' =

3,2, H-3 '); 5.13 (dd, 1H, J22 = 6.4, J2r = 3.0, H-2 '); 6.45 (d, 1H, JV2 = 3.0, H-1 '); 7.19-7.22 (m, 6H, H-o-Tr); 7.32-7.37 (m, 9H, H-m, p-Tr); 7.38 (d, 1H, J56 = 3.8, H-5); 7.48 (d, 1H, J6 5 = 3.8, H-6); 7.61 (d, 1H, J25 =

1,4, H-2-imidazole); 7.90 (d, 1H, J52 = 1.4, H-5-imidazole); 8.75 (s, 1H, H-2) .13CNMR (125.7MHz, CDCb): - 5.48 and -5.36 (CH3SO; 18.38 (SiC (CH3b); 25.50 ((CH3) 2C); 25.93 ((CH3) 3C); 27.35 ((CH3) 2C); 63.35 (CH2-5 '); 75.87 (C-Tr); 80.95 (CH-3' ); 84.92 (CH-2 '); 85.97 (CH-4'); 89.96 (CH-1 '); 103.38 (CH-

5); 114.06 (C (CH3) 2); 114.81 (C-4a); 123.27 (CH-5-imidazole); 126.07 (CH-6); 128.19 (CH-m, p-

Tr); 129.80 (CH-o-Tr); 140.17 (CH-2-imidazole); 140.51 (C-4-imidazole); 142.08 (C - / - Tr); 151.32 (CH-2); 151.83 (C-4); 151.92 (C-7a). MS FAB, m / z (rel.%): 243 (100), 434 (15), 714 (5) [M + H]. HR MS (FAB): Calculated for C42H4sN5O4Si [M + H] 714.3476, found 714.3447.

Example 10. 4- (Pyridine-3-yl) -7- (P-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (3k)

[0178]

image25

[0179] Compound 2k (359 mg, 0.74 mM) is treated with 90% aqueous TFA (0.5 ml) for one hour at room temperature. The volatiles are removed to the ford and the residue is sometimes co-evaporated with MeOH. Silica chromatography (5% ^ 6% MeOH in CHCb) generated nucleoside 3k (270 mg, 110%) as a colorless bilious solid. Crystallization from MeOH / AcOEt / hexane gave a white hygroscopic powder (146 mg, 60%). The mother liquors were purified by reversed phase chromatography generating additional portions of the 3k compound (57 mg, 23%) as a white powder after lyophilization. The total production of the 3k product is 83%. 1H NMR (600 MHz, DMSO-cfe): 3.58 (ddd, 1H, Jgem = 11.9, JSb, oH = 5.5, JSb, 4 '= 3.9, H-5'b); 3.66 (ddd, 1H, Jgem = 11.9, JSa, oH = 5.2, Js, 4 '= 3.9, H-5'a); 3.95 (td, 1H,

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J * s = 3.9, J4'3 = 3.3, H-4 '); 4.15 (ddd, 1H, Jjoh = 4.7, J32 = 4.6, Js # = 3.3, H-3 '); 4.47 (ddd, 1H, J2r = 6.2, J2oh =

6.1, J2.3 '= 4.6, H-2'); 5.13 (dd, 1H, Joh, 5 '= 5.5, 5.2, OH-5'); 5.25 (d, 1H, Joh, 3 = 4.7, OH-3 '); 5.44 (d, 1H, Joh, 2 =

6.1, OH-2 '); 6.30 (d, 1H, Jr2 = 6.2, H-1 '); 7.08 (d, 1H, J56 = 3.8, H-5); 7.63 (ddd, 1H, J54 = 7.9, J56 = 4.8, J52 = 0.9, H-5-py); 8.02 (d, 1H, Je5 = 3.8, H-6); 8.53 (ddd, 1H, J45 = 7.9, J42 = 2.3, J46 = 1.7, H-4-py); 8.76 (dd, 1h, J65 = 4.8, J6 4 = 1.7, H-6-py); 8.94 (s, 1 H, H-2); 9.32 (dd, 1H, J24 = 2.3, J25 = 0.9, H-2-py). 13C NMR (151 MHz, DMSO-de): 61.79 (CH2-5 '); 70.86 (CH-3 '); 74.40 (CH-2 '); 85.52 (CH-4 '); 86.97 (CH-1 '); 100.97 (CH-5); 115.98 (C-4a); 124.36 (CH-5-py); 128.84 (CH-6); 133.41 (C-3-py); 136.35 (CH-4-py); 149.49 (CH-2-py); 151.21 (CH-6- py); 151.36 (CH-2); 152.19 (C-7a); 153.89 (C-4). IR (KBr): v = 1679, 1566, 1517, 1457, 1420, 1206, 1132, 1087, 1045, 1030 cm'1. MS FAB, m / z (rel.%): 329 (100) [M + H]; HR MS (FAB): Calculated for C16H17N4O4 [M + H] 329.1250, found 329.1238.

[0180] Intermediate compound 2k is prepared as follows:

to. 7- {2,3-0-Isopropylidene-5-0- (ferc-butyldimethylsilyl) -p-D-ribofurans M} -4- (pyridma-3-yl) -7H-

pyrrolo [2,3-d] pyrimidma (2k). A mixture purged with argon of chlorodeazapurine 1 ribosides (306 mg, 0.695 mM), pyridine-3-borbonic acid (128 mg, 1.04 mM), K2CO3 (192 mg, 1.39 mM) and Pd (PPh3) 4 (40 mg, 0.03 mM) endimethoxyethane (3mL) / H2O (1 mL) is stirred at 100 ° C for 3 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous NH4Cl (sat., 20 mL), the aqueous phase is reextracted with chloroform (3 X 5 milliliters). The organic extracts collected are dried over MgSO4, the volatiles are removed to the ford and the residue is exposed to silica chromatography (hexanes-AcOEt, 2: 1) generating the product 2k in the form of a yellowish oil (318 mg, 95%) . 1H NmR (600 MHz, CDCl3): 0.07 and 0.08 (2 X s, 2 X 3H, CH3Si); 0.91 (s, 9H, (CH3) 3C); 1.41 and 1.67 (2 X q, 2 X 3H, J = 0.6, (CH3) 2C); 3.82 (dd, 1H, Jgem = 11.3, JSb4 =

3.7, H-5'b); 3.92 (dd, 1H, Jgem = 11.3, J3'a4 '= 3.6, H-5'a); 4.38 (ddd, 1H, J ^ s = 3.7, 3.6, J43 = 3.1, H-4 '); 4.99 (ddd, 1H, J32 = 6.2, J? * = 3.1, J3r = 0.4, H-3 '); 5.13 (dd, 1H, J23 = 6.2, J2r = 3.0, H-2 '); 6.51 (d, 1H, Jr2 = 3.0, H-1 '); 6.84 (d, 1H, J56 = 3.8, H-5); 7.50 (ddd, 1H, J54 = 7.9, J56 = 4.6, J52 = 0.9, H-5-py); 7.65 (d, 1H, J6.5 = 3.8, H-6); 8.43 (ddd, 1H, J45 = 7.9, J4.2 = 2.2, JA, 6 = 1.7, H-4-py); 8.75 (dd, 1H, J6.5 = 4.6, J64 = 1.7, H-6-py); 9.01 (s, 1H, H-2); 9.33 (dd, 1H, J24 = 2.2, J25 = 0.9, H-2-py). 13C NMR (151 MHz, CDCl3): - 5.49 and -5.38 (CH3Si); 18.38

(C (CHa) a); 25.47 ((CH3) 2C); 25.90 ((CH3) 3C); 27.37 ((CH3) 2C); 63.42 ((CH2-5 '); 80.89 (CH-3'); 85.06 (CH-2 '); 86.10 (CH-4'); 90.30 (CH-1 ') ; 100.83 (CH-5); 114.20 (C (CHah); 116.54 (C-4a); 123.79 (CH-5-py); 127.48 (CH-6); 133, 92 (C-3-py); 136.08 (CH-4-py); 149.81 (CH-2-py); 150.84 (CH-6-py); 151.65 (C-7a) ; 151.79 (CH-2); 154.63 (C-4) .MSFAB, m / z (rel.%): 73 (45), 196 (35), 483 (100) [M + H]; HR MS (FAB): calcd for C ^ H ^ N ^ Si [M + H] 483.2428, found 483.2433.

Example 11. 4-Hydroxymethyl-7- (P-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (31).

[0181]

image26

[0182] Compound 21 (326 mg, 0.75 mM) is treated with 90% aqueous TFA (1 ml) for one hour at room temperature. The volatile elements are removed to the ford and the residue is co-evaporated several times with MeOH. Silica chromatography ((7% ^ 10% MeOH in CHCl3) generates a free nucleoside 31 (194 mg, 92%) in the form of a yellowish glassy solid. After a reverse phase chromatography, the compound crystallizes from MeOH. 1H NMR (600 MHz, DMSO-de): 3.55 (ddd, 1H, Jgem = 11.9, J5bOH =

5.7, Jsb4 '= 4.0, H-5'b); 3.63 (ddd, 1H, Jgem = 11.9, Jsaoh = 5.3, J3'a4 '= 4.0, H-5'a); 3.92 (q, 1H, Jas = 4.0, J * 3 '=

3.3, H-4 '); 4.11 (td, 1H, J32 = 5.1, J3oh = 4.8, Js # = 3.3, H-3 '); 4.42 (td, 1H, J2oh = 6.4, J2r = 6.2, J23 = 5.1, H-2 '); 4.82 (d, 2H, Jch2, oh = 5.8, CH2OH); 5.08 (t, 1H, Joh, 5 = 5.7, 5.3, OH-5 '); 5.18 (d, 1H, Joh, 3 = 4.8, OH-3 '); 5.35 (d, 1H, Joh, 2 '= 6.4, OH-2'); 5.61 (d, 2H, Joh, ch2 = 5.8, HOCH2); 6.21 (d, 1H, Jr, 2 = 6.2, H-1 '); 6.88 (dd, 1H, J3.6 = 3.7, J52 = 0.4, H-5); 7.79 (d, 1H, J65 = 3.7, H-6); 8.69 (s, 1 H, H-2). 13C NMR (151 MHz, DMSO-de): 61.80 (CH2-5 '); 64.25 (CH2OH); 70.80 (CH-3 '); 74.20 (CH-2 '); 85.30 (CH-4 '); 86.84 (CH-1 '); 101.24 (CH-5); 116.50 (C-4a); 126.71 (CH-6); 150.51 (CH-2); 151.49 (C-7a); 162.28 (C-4). IR (KBr): v = 1680, 1598, 1517, 1444, 1356, 1204, 1137, 1086 cm-1. MS FAB, m / z (rel.%): 176 (90), 282 (100) [M + H]. HR MS (FAB): calcd for C12H16N3O5 [M + H] 282,1090, found 282,1083. Anal. Calcd for C12H15N3O5: C, 51.24; H, 5.38; N, 14.94. Found: C, 50.95; H, 5.40; N, 14.94.

[0183] Intermediate compound 21 is prepared as follows:

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to. 4- (BenzoMoximetM) -7- [2,3-0-isopropMidene-5-0-ferc-butMdimetMsMM- (3-D-ribofuransM] -

7H-pyrrolo [2,3-d] pyrimidma (2l) and 4-hydroxymethN-7- [2,3-0-isopropMidene-5-0-ferc-butNdimetNsMM-P- D-ribofuranosyl] -7H-pyrrolo [2 , 3-d] pyrimidine (21). To a mixture purged with argon of chlorine ribosides 11 (440 mg, 1 mM) and Pd (PPhi3) 4 (58 mg, 0.05 mM) is added a 0.9 M solution of benzoyloxymethylzinc iodide in THF (3 , 33 ml, 3 mM). The mixture is stirred at room temperature for 15 hours and then saturated NH4Cl (20 mL) is added followed by extraction with chloroform (25 ml, 2 X 5 milliliters). The organic extracts are washed with an EDTA solution, dried over MgSO4 and evaporated. Column chromatography of the residue in silica (hexanes-AcOEt, 8: 1 ^ 2: 1) generating 196 mg of compound 21 (54%) and 103 mg of compound 21 '(23%). Compound 21 can be quantitatively converted to compound 21 'by treatment with 1 M NaOMe / MeOH (10 mol%) for 2 hours followed by neutralization with an excess of Dowex 50 (a pyridinium form) and through evaporation. Compound 21: colorless oil. 1H NMR (600 MHz, CDCh): 0.03 and 0.04 (2 X s, 2 X 3H, CHaSi); 0.87 (s, 9H, (CHa) BC); 1.39 (q, 3H, J = 0.6, (CHa ^ C); 1.65 (q, 3H, J = 0.6, (CHs ^ C); 3.79 (dd, 1 H, Jgem = 11.2, J5'b4 '= 3.9, H-5'b); 3.87 (dd, 1H, Jgem = 11.2, JSa4' = 3.7, H-5'a); 4 , 34 (q, 1H, JAS =

3,9,3,7, J4'3 = 3,1, H-4 '); 4.97 (ddd, 1H, JS2 = 6.5, Js # = 3.1, Jar = 0.4, H-3 '); 5.11 (dd, 1H, J2a = 6.5, J2r = 3.0, H-2 '); 5.71 (s, 2H, CH2O); 6.44 (d, 1H, Jr2 = 3.0, H-1 '); 6.68 (d, 1H, J56 = 3.7, H-5); 7.46 (m 2H, H- m-Ph); 7.50 (d, 1H, J6 5 = 3.7, H-6); 7. 59 (m, 1H, H-p-Ph); 8.12 (m, 2H, H-o-Ph); 8.90 (s, 1H, H-2). 13C NMR (151MHz, CDCls): - 5.52 and -5.41 (CHsSi); 18.35 (CfCHsk); 25.45 ((CHs) 2C); 25.87 ((CH3feC); 27.33 ((CHs) 2C); 63.36 (CH2-5 '); 65.90 (CH2O); 80.88 (CH-3'); 84.92 (CH -2 '); 86.12 (CH-4'); 90.26 (CH-1 '); 100.32 (CH-5); 114.17 (C (CH3) 2); 117.21 (C -4a); 126.99 (CH-6); 128.50 (CH-m-Ph); 129.54 (C - / - Ph); 129.87 (CH-o-Ph); 133.31 ( CH-p-Ph); 151.15 (C-7a); 151.26 (CH-2); 155.99 (C-4); 166.13 (CO). MS FAB, m / z (rel. %): 540 (100) [M + H] .HRMS (FAB): calcd for C28H38N3O6Si [M + H] 540.2530, found 540.2545. Compound 21 ': yellowish oil. 1H NMR (600 MHz, CDCl3) : 0.05 and 0.06 (2 X s, 2 X

3H, CH3Si); 0.90 (s, 9H, (CH3) 3C); 1.39 (q, 3H, J = 0.6, (CH3) 2C); 1.66 (q, 3H, J = 0.6, (CH3) 2C); 3.80 (dd, 1H, Jgem = 11.2, J5'b4 '= 3.8, H-5'b); 3.88 (dd, 1H, Jgem = 11.2, JSa4 '= 3.6, H-5'a); 4.35 (q, 1H, J4 5 '= 3.8, 3.6, J4'3 = 3.1, H-4'); 4.97 (ddd, 1H, JS2 = 6.3, J34 '= 3.1, Jar = 0.4, H-3'); 5.01 (s, 2H, CH2O); 5.09 (dd, 1H, J2 ', a = 6.3, J2, r = 3.1, H-2 ’); 6.45 (d, 1h, Jr, 2 '= 3.1, H-1'); 6.57 (d, 1H, Ja, 6 = 3.7, H-5); 7.53 (d, 1H, J6.5 = 3.7, H-6); 8.86 (s, 1H, H-2). 13C NMR (151 MHz, CDCh): -5.50 and -5.39 (CH3SO; 18.38 (C (CH3) s); 25.47 ((CH3) 2C); 25.90 ((CH3) sC ); 27.36 ((CH3) 2C); 61.88 (CH2O); 63.38 (CH2-5 '); 80.88 (CH-3'); 84.97 (CH-2 '); 86 , 02 (CH-4 '); 90.23 (CH-1'); 99.37 (CH-5); 114.20 (C (CH3) 2); 115.41 (C-4a); 126, 57 (CH-6); 150.27 (C-7a); 150.70 (CH-2); 159.27 (C-4).

Example 12. 4- (Furan-3-N) -7- (P-D-nbofuransN) -7H-pyrrolo [2,3-c /] pmmidma (3m).

[0184]

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[0185] To a mixture purged with argon free ribosides 4 (226 mg, 0.79 mM), furan-3-boronic acid (111 mg, 0.99 mM), Cs2 (CO3) 2 (774 mg, 2, 1 mM) a previously repaired solution of Pd (OAc) 2 (9 mg, 0.04 mM) and TPPTS (56 mg, 0.099 mM) in water / CH3CN (2: 1, 3 mL) is added. The reaction mixture is stirred at 100 ° C for 3 hours. After cooling, the mixture is neutralized by adding aqueous HCl (3M sol.), It is co-evaporated with silica chromatography on a silica column (4.5% MeOH in CHCh) generating the product 3m (172 mg, 69 %) in the form of a yellowish solid. The compound crystallizes MeOH / CHCh / hexane as a white powder. 1H NMR (500 MHz, DMSO-cfe): 3.57 (ddd, 1H, Jgem = 11.9, JsbOH = 5.8, J5’64 = 4.0, H-5'b); 3.66 (ddd, 1H, Jgem = 11.9, JaaOH = 5.3, JSb4 '= 4.0, H-5'a); 3.94 (td, 1H, J * s = 4.0, Jra = 3.4, H-4 '); 4.14 (ddd, 1H, Ja2 '= 5.1, JaOH = 4.9, Jar = 3.4, H-3'); 4.45 (ddd, 1H, J2oh = 6.3, J2r = 6.1, J2a = 5.1, H-2 '); 5.09 (dd, 1H, Joh5 '= 5.8, 5.3, OH-5'); 5.18 (d, 1H, Joh3 = 4.9, OH-3 '); 5.37 (d, 1H, Joh2 '= 6.3, OH-2'); 6.24 (d, 1H, Jr2 =

6.1, H-1 '); 7.10 (d, 1H, J56 = 3.8, H-5); 7.26 (dd, 1H, J45 = 1.9, J42 = 0.8, H-4-furyl); 7.90 (dd, 1H, Ja4 = 1.9, J52 = 1.5, H-5-furyl); 7.92 (d, 1H, Je5 = 3.8, H-6); 8.74 (dd, 1H, J25 = 1.5, J24 = 0.8, H-2-furyl); 8.78 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 61.73 (CH2-5 '); 70.73 (CH-3 '); 74.20 (CH-2 '); 85.32 (CH-4 '); 86.92 (CH-1 '); 100.86 (CH-5); 109.55 (CH-4-furyl); 114.65 (C-4a); 125.19 (C-3- furyl); 127.77 (CH-6); 144.74 (CH-5-furyl); 145.01 (CH-2-furyl); 150.15 (C-4); 151.12 (CH-2); 151.73 (C-7a). MS FAB, m / z (rel.%): 73 (100), 217 (45), 318 (55) [M + H]. HR MS (FAB): calcd for C15H16N3O5 [M + H] 318,1090, found 318,1086.

Example 13. 7- (P-D-Ribofuranosyl) -4- (thiophen-3-yl) -7H-pyrrolo [2,3-d] pyrimidine (3n).

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[0187] To a mixture purged with free riboside argon 4 (226 mg, 0.79 mM), thiophene-3-boronic acid (168 mg, 0.99 mM), Cs2 (COs) 2 (774 mg, 2, 1 mM) a previously prepared solution of Pd (OAc) 2 (9 mg, 0.04 mM) and TPPTS (56 mg, 0.099 mM) in water / CHsCN (2: 1, 3 ml_) is added. The reaction mixture is stirred at 100 ° C for 3 hours. After cooling the mixture is neutralized by the addition of aqueous HCI (3M sol.), It is co-evaporated with silica and exposed to a chromatograph in the silica column (4.5% MeOH in CHCL) generating at 3n product (176 mg, 67%) in the form of a white foam. The compound is crystallized from water in the form of white fine needles. 1H NMR (500 MHz, DMSO-cfe): 3.57 (ddd, 1H, Jgem = 11.9, J5’bOH = 5.7, J5> b4 ’= 4.0, H-5’b); 3.66 (ddd, 1H, Jgem = 11.9, J5’aOH = 5.4, J5’b4- = 4.0, H-5’a); 3.94 (td, 1H, J4 "5" = 4.0, J4'3 "= 3.3, H-4"); 4.14 (ddd, 1H, J3’2 = 5.1, J3’oh = 4.8, J3 “4’ = 3.3, H-3 ”); 4.46 (ddd, 1H, J2’0h = 6.4, J? R = 6.2, J2’3 =

5.1, H-2 ’); 5.11 (dd, 1H, J0H5 ’= 5.7, 5.4, OH-5’); 5.20 (d, 1H, JOH3 = 4.8, OH-3 ’); 5.40 (d, 1H, JOH2 = 6.4, OH-2 ’); 6.26 (d, 1H, Jr2 = 6.2, H-1 ’); 7.16 (d, 1H, J56 = 3.8, H-5); 7.75 (dd, 1H, J54 = 5.0, J52 = 2.9, H-5-thienyl); 7.95 (d, 1H, J65 = 3.8, H-6); 7.96 (dd, 1H, J45 = 5.0, J42 = 1.3, H-4-thienyl); 8.55 (dd, 1H, J25 = 2.9, J24 = 1.3, H-2- thienyl); 8.81 (s, 1H, H-2). 1X NMR (125.7 MHz, DMSO-cfe): 61.73 (CH2-5 ’); 70.75 (CH-3 ’); 74.24 (CH-2 ’); 85.34 (CH-4 ’); 86.91 (CH-1 ’); 101.10 (CH-5); 114.68 (C-4a); 127.30 (CH-5-thienyl); 127.60 (CH-6); 128.07 (CH-4- thienyl); 128.70 (CH-2-thienyl); 140.06 (C-3-thienyl); 151.08 (CH-2); 151.59 (C-4); 152.19 (C-7a). IR (KBr): v = 1633, 1572, 1517, 1459, 1349, 1239, 1119, 1087, 1049 cm'1. MS FAB, mlz (rel.%): 202 (55), 223 (40), 334 (100) [M + H]. HR MS (FAB): calcd for Ci5Hi6N304S [M + H] 334.0862, found 334.0857. Anal. Calcd for Ci5Hi5N3O4S 0.45H2O: C, 52.76; H, 4.69; N, 12.31. Found: C, 52.54; H, 4.43; N, 12.10.

Example 14. 4- (1 H-Pyrrol-3-yl) -7- (p-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (3rd).

[0188]

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[0189] To a mixture purged with free riboside argon 4 (100 mg, 0.35 mM), 1- (triisopropylsilyl) -1H-pyrrole-3-boronic acid (112 mg, 0.42 mM), Na2 (CO3 ) 2 (111 mg, 1.06 mM) a previously prepared solution of Pd (OAc) 2 (4 mg, 0.018 mM) and TPPTS (25 mg, 0.044 mM) in water / CH3CN (2: 1, 3 mL) is added ). The reaction mixture is stirred at 100 ° C for 5 hours. After cooling, the mixture is neutralized by the addition of aqueous HCl (3M sol.) And purified by reverse phase chromatography generating the product 3o (61 mg, 55%) as a white solid. The compound crystallizes from water providing white fine needles. 1H NMR (500 MHz, DMSO-cfe): 3.56 (ddd, 2H, Jgem = 12.0, J5bOH = 5.9, J5b4 = 3.9, H-5’b); 3.65 (ddd, 2H, Jgem = 12.0, JffaOH = 5.3, Jffa4 '= 3.9, H-5'a); 3.92 (td, 1H, J * 5 ’= 3.9, J *, 3’ = 3.4, H-4 ’); 4.09 (ddd, 1H, J32 = 5.1, J3oh = 4.8, J * 4 ’= 3.4, H-3’); 4.45 (ddd, 1H, JZoh = 6.4, Jzr = 6.2, JZ3 = 5.1, H-2 ’);

5.13 (dd, 1H, Joh5 = 5.9, 5.3, OH-5 ’); 5.15 (d, 1H, Joh3 ’= 4.8, OH-3’); 5.34 (d, 1H, Joh2 ’= 6.4, OH-2’); 6.19 (d, 1H, J1’2 ’= 6.2, H-1’); 6.90 (td, 1 H, J45 = J4nh = 2.7, J4 2 = 1.8, H-4-pyrr); 6.92 (td, 1H, J54 = J5NH = 2.7, J52 = 1.8, H-5-pyrr); 7.01 (d, 1H, J5 6 = 3.8, H-5); 7.76 (d, 1H, JQ5 = 3.8, H-6); 7.77 (dt, 1H, J2NH = 2.9, J24 = J25 = 1.8, H-2- pyrr); 8.63 (s, 1 H, H-2); 11.40 (bs, 1H, NH). 13C NMR (125.7 MHz, DMSO-d6): 61.84 (CH2-5 ’); 70.81 (CH-3 ’); 74.08 (CH-2 ’); 85.25 (CH-4 ’); 86.99 (CH-1 ’); 101.31 (CH-5); 108.11 (CH-4-pyrr); 113.47 (C-4a); 119.72 (CH-5- pyrr); 121.17 (CH-2-pyrr); 122.39 (C-3-pyrr); 126.48 (CH-6); 151.11 (CH-2); 151.57 (C-7a); 153.79 (C-4). GO

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(KBr): v = 1628, 1577, 1508, 1458, 1433, 1351, 1270, 1230, 1188, 1126, 1084, 1054, 1014 cm-1. MS FAB, m / z (rel.%): 73 (100), 217 (45), 318 (55) [M + H]. HR MS (FAB): calcd for C15H16N3O5 [M + H] 318,1090, found 318,1086. Anal. Calcd for C14H15N5O4M5H2O: C, 52.61; H, 5.56; N, 16.36. Found: C, 52.79; H, 5.51; N, 16.21.

Example 15. 7- (p-D-RibofuransN) -4- (selenophene-2-N) -7H-pyrrolo [2,3-d] pinmidma (3p).

[0190]

image30

[0191] To a mixture purged with free riboside argon 4 (219 mg, 0.77 mM), selenophene-2-boronic acid (168 mg, 0.96 mM), Cs2 (C03) 2 (750 mg, 2, 3 mM) a previously prepared solution of Pd (OAc) 2 (9 mg, 0.04 mM) and TPPTS (54 mg, 0.095 mM) in water / CH3CN (2: 1, 3 ml_) is added. The reaction mixture is stirred at 100 ° C for 3 hours. After cooling, the mixture is neutralized by the addition of aqueous HCI (3M sol.), Co-evaporated with silica and exposed to a chromatograph on a silica column (4.5% MeOH in CHCI3) generating the product. 3p (188 mg, 64%) in the form of a yellow solid. The compound crystallizes from MeOH facilitating beige crystals. 1H NMR (600 MHz, DMSO-cfe): 3.57 (ddd, 1H, Jgem = 12.0, Js’b.orF 5.8, J5’b4 '= 4.1, H-5’b); 3.66 (ddd, 1H, Jgem = 12.0, J5aoH = 5.2, J5’b4- = 4.1, H-5’a); 3.94 (td, 1H, J4 «5’ = 4.1, J4’3 ’=

3.3, H-4 ’); 4.13 (td, 1H, J3’2 ’= ^ oh = 4.9, J3“ 4 ’= 3.3, H-3”); 4.44 (ddd, 1H, J2 0h = 6.3, J? R = 6.1, J2’3 = 4.9, H-2 ’); 5.11 (dd, 1H, J0H 5 ’= 5.8, 5.2, OH-5’); 5.20 (d, 1H, J0H3 = 4.9, OH-3 ’); 5.41 (d, 1H, J0H2 = 6.3, OH-2 ’); 6.25 (d, 1H, Jr, 2 = 6.1, H-1 ’); 7.20 (d, 1H, J5.6 = 3.8, H-5); 7.54 (dd, 1H, J4.5 = 5.6, J4.3 = 4.1, H-4-selenophenyl); 7.97 (d, 1H, J6.5 = 3.8, H-6); 8.38 (dd, 1H, J3.4 = 4.1, J3.5 = 1.0, H-3-selenophenyl); 8.46 (dd, 1H, J5.4 = 5.6, J5.3 = 1.0, H-5- selenophenyl); 8.72 (s, 1H, H-2). 13C NMR (151 MHz, DMSO -c / 6): 61.73 (CH2-5 ’); 70.77 (CH-3 ’); 74.30 (CH-2 ’); 85.40 (CH-4 ’); 86.96 (CH-1 ’); 101.07 (CH-5); 112.44 (C-4a); 128.52 (CH-6); 131.81 (CH-3-selenophenyl); 131.99 (CH-4-selenophenyl); 136.73 (CH-5-selenophenyl); 149.41 (C-2-selenophenyl); 151.08 (CH-2); 151.57 (C-4); 152.31 (C-7a). IR (KBr): v = 1566, 1509, 1448, 1420, 1350, 1244, 1211, 1131, 1098, 1051 cm'1. MS FAB, m / z (rel.%): 382 (100) [M + H]. HR MS (FAB): calcd for Ci5Hi6N304Se [M + H] 382.0306, found 382.0299. Anal. Calcd for Ci5Hi5N304Se: C, 47.38; H, 3.98; N, 11.05. Found: C, 46.99; H, 3.99; N, 10.59.

Example 16. 4- (1 H-Pirazol-5-yl) -7- (p-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (3q).

[0192]

image31

[0193] To a mixture purged with argon of free ribosides 4 (100 mg, 0.35 mM), 1H-pyrazol-5-boronic acid (47 mg, 0.42 mM), Na2 (C03) 2 (111 mg, 1.06 mM) a previously prepared solution of Pd (0Ac) 2 (4 mg, 0.018 mM) and TPPTS (25 mg, 0.044 mM) in water / CH3CN (2: 1, 3 mL) is added. The reaction mixture is stirred at 100 ° C for 5 hours. After cooling, the mixture is neutralized by the addition of aqueous HCl (sol of 3 M) and purified by reverse phase chromatography generating the product 3q (71 mg, 64%) and as an amorphous glassy solid. The compound is lyophilized. 1H NMR (600 MHz, DMSO-cfe): 3.56 (ddd, 1H, Jgem = 11.9, J5'b, 0H = 5.7, J & 6.4 '= 4.0, H-5'b) ; 3.63 (ddd, 1H, Jgem = 11.9, J5a, 0H = 5.1, J5’a, 4 ’= 4.0, H-5’a); 3.93 (td, 1H, J 4 5 = 4.0, J4’3 ’= 3.4, H-4’); 4.13 (ddd, 1H, Jff2 ’= 5.1, J3oh = 4.9, J * 4’ = 3.4, H-3 ’); 4.45 (td, 1H, JZr = Jzoh = 6.2, Jz3 = 5.1, H-2 ’); 5.11 (dd, 1H, Joh5 ’= 5.7, 5.1, OH-5’); 5.19 (d, 1H, Joh3 ’= 4.9, OH-3’); 5.39 (d, 1H, Joh2 ’= 6.2, OH-2’); 6.24 (d, 1 H, Jrz = 6.2, H-1 ’); 7.07 (s, 1 H, H-4-pyrazolyl); 7.21 (d, 1H, J56 = 3.5, H-5); 7.86 (d, 1H, J65 =

3.5, H-6); 7.93 (s, 1 H, H-3-pyrazolyl); 8.79 (s, 1 H, H-2); 13.40 (s, 1 H, NH). 13C NMR (151 MHz, DMSO-da): 61.83 (CH2-5 ’); 70.84 (CH-3 ’); 74.23 (CH-2 ’); 85.35 (CH-4 ’); 86.87 (CH-1 ’); 102.79 (CH-5); 105.17 (CH-4-pyrazolyl); 114.28 (C-4a); 127.58 (CH-6); 130.02 (CH-3-pyrazolyl); 150.70 (C-5-pyrazolyl); 150.92 (C-4); 151.15

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(CH-2); 152.10 (C-7a) ;. MS FAB, m / z (rel.%): 318 (100) [M + H]. HR MS (FAB): calcd for C14H16N5O4 [M + H] 3l8,1202, found318,1200.Anal.Calcd for C14H15N5O4 H2O: C, 50.15; H, 5.11; N, 20.89. Found: C, 50.04; H, 4.92; N, 20.55.

Example 17. 4- (1H-Pirazol-4-M) -7- (PD-ribofuransN) -7H-pyrrolo [2,3-d] pmmidma (3r) and 1,4-Bis {7- (PD-ribofuranosil ) -7H-pyrrolo [2,3-d] pyrimidine-4-yl} -1H-pyrazole (3r ').

[0194]

image32

[0195] To a mixture purged with free riboside argon 4 (226 mg, 0.77 mM), pyrazol-4-boronic acid (107 mg, 0.96 mM), Cs2 (CO3) 2 (753 mg, 2, 3 mM) a previously prepared solution of Pd (OAc) 2 (9 mg, 0.04 mM) and TPPtS (55 mg, 0.097 mM) in water / CH3CN (2: 1, 3 mL) is added. The reaction mixture is stirred 150 ° C for 20 minutes in a microwave oven. After cooling the mixture is neutralized by the addition of aqueous HCl (3M sol.) And purified by reverse phase chromatography providing the desired product 3r, 4-pyrazolyl (30 mg, 12%) as a colorless glassy solid. and a 3r- dimer (40 mg, 18%) in the form of a colorless solid. 3rd: 1H NMR (600 MHz, DMSO-d6): 3.56 (ddd, 1H, Jgem = 11.9, J5'bOH = 5.8, J5'b4 '= 4.0, H-5'b) ; 3.65 (ddd, 1H, Jgem = 11.9, J? AOH = 5.3, J & a4 '= 4.0, H-5'a); 3.92 (td, 1H, J45 '= 4.0, J43' = 3.3, H-4 ');

4.13 (ddd, 1H, J32 = 5.2, Jsoh = 4.9, J24 = 3.3, H-3 '); 4.45 (ddd, 1H, J2oh = 6.4, J2r = 6.2, J23 = 5.2, H-2 '); 5.12

(dd, 1H, Joh5 = 5.8, 5.3, OH-5 '); 5.18 (d, 1H, Joh3 '= 4.9, OH-3'); 5.38 (d, 1H, Joh2 '= 6.4, OH-2'); 6.22 (d, 1H,

Jr2 '= 6.2, H-1'); 7.13 (dd, 1H, J56 = 3.8, J5V = 0.3, H-5); 7.86 (d, 1H, J65 = 3.8, H-6); 8.35 and 8.67 (2 X bs, 2 X 1H, H-pyrazole); 8.71 (s, 1 H, H-2); 13.41 (bs, 1H, NH). 13C NMR (151 MHz, DMSO-d6): 61.79 (CH2-5 '); 70.79 (CH-3 '); 74.18 (CH-2 '); 85.32 (CH-4 '); 86.94 (CH-1 '); 101.02 (CH-5); 113.93 (C-4a); 120.20 (C-2-pyrazole); 127.22 (CH-6); 129.80 and139.26 (CH-3,5-pyrazole); 151.20 (CH-2); 151.21 (C-4); 151.65 (C-7a). MS FAB, m / z (rel.%): 318 (100) [M + H] .HRMS (FAB): calcdparaC14H16NaO4 [M + H] 318,1202, found 318,1195. 3r ': 1H NMR (600 MHz, DMSO-de): 3.58 and 3.67 (2 X m, 2 X 2H, H-5'); 3.95 and 3.96 (2 X td, 2 X

1H, J4'5 '= 4.0, J4'3' = 3.7, H-4 '); 4.15 (ddd, 2H, J32 = 5.0, J3oh = 4.7, J24 = 3.7, H-3 '); 4.46 and 4.47 (2 X ddd, 2 X

1H, J2'oh = 6.3, J2V = 6.1, J2'3 '= 5.0, H-2'); 5.11 and 5.12 (2 X t, 2 X 1H, Joh5 = 5.5, OH-5 '); 5.21 and 5.24 (2 X d, 2 X 1H, Joh 3 '= 4.7, OH-3'); 5.42 and 5.45 (2 X d, 2 X 1H, JoH2 = 6.3, OH-2 '); 6.27 and 6.31 (2 X d, 2 X 1H, JV2 = 6.1, H- 1 '); 7.25 (d, 1H, J56 = 3.8, H-5); 7.28 (dd, 1H, J56 = 3.7, J5V = 0.4, H-5); 7.98 (d, 1H, J65 = 3.8, H-6); 8.00 (d, 1H, J6 5 = 3.7, H-6); 8.81 and 8.84 (2 X s, 2 X 1H, H-2); 8.88 and 9.53 (2 X d, 2 X 1H, J = 0.8, H-pyrazole). 13C NMR (151 MHz, DMSO-de): 61.72 and 61.77 (CH2-5 '); 70.81 (CH-3 '); 74.29 and 74.46 (CH-2 '); 85.42 and 85.53 (CH-4 '); 86.90 and

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87.05 (CH-1 ’); 100.85 and 102.71 (CH-5); 107.04 and 114.70 (C-4a); 123.33 (C-2-pyrazole); 128.18 and 128.23 (CH-6); 128.36 and 143.78 (CH-3,5-pyrazole); 148.36 and 149.24 (C-4); 150.58 and 151.29 (CH-2); 151.95 and 153.84 (C-7a). MS FAB, m / z (rel.%): 567 (100) [M + H]. HR MS (FAB): calcd for C25H27N8O8 [M + H] 567.1952, found 567.1958.

Example 18. 4- (Pmdm-2-N) -7- (p-D-ribofuransN) -7H-pyrrolo [2,3-d] pinmidma (3s).

[0197] An argon purged mixture of 6-chloro-7-deazapurine 4 ribosides (220 mg, 0.77 mM), 2- (tributylstanyl) pyridine (320 mL, 1.16 mM) and PdCh (PPh3) 2 (27 mg, 0.038 mM) in DMF (3 mL) is stirred at 100 ° C for 24 hours. The volatiles are removed in vacuo and the residue is co-evaporated several times with MeOH and toluene. A suspension of the residue in MeOH / CH2Cl2 is co-evaporated with silica and dried in the form of KF aerosol and a subsequent chromatograph is executed in the silica column (7% MeOH in CHCI3) which generated the product 3s (128 mg , 51%) in the form of a yellowish oil. The compound is crystallized from MeOH / AcOEt in the form of a white powder. 1H NMR (600 MHz, DMSO-cfe): 3.57 (ddd, 1H, Jgem = 11.9, Js’b.orF

5.5, J5’b4 ’= 4.0, H-5’b); 3.66 (ddd, 1H, Jgem = 11.9, J5’aOH = 5.3, J5> a4 “= 4.1, H-5’a); 3.95 (ddd, 1H, J4 "5" = 4.1, 4.0, J4'3 "= 3.3, H-4"); 4.14 (td, 1H, J3’2 ’= ^ oh = 4.7, J3“ 4 ’= 3.3, H-3”); 4.46 (ddd, 1H, J2 r = 6.2, J? 0h = 6.1, J2’3 ’= 4.7, H-2’); 5.10 (dd, 1H, J0H5 = 5.5, 5.3, OH-5 ’); 5.22 (d, 1H, J0h3 = 4.7, OH-3 ’); 5.41 (d, 1H, J0H2 = 6.1, OH-2 ’); 6.30 (d, 1H, Jr z = 6.2, H-1 ’); 7.47 (d, 1H, J5Q = 3.7, H-5); 7.56 (ddd, 1H, J54 = 7.5, J5Q = 4.7, J53 = 1.2, H-5-py); 7.96 (d, 1H, J65 = 3.7, H-6); 8.03 (ddd, 1H, J43 = 7.9, J45 = 7.5, J46 = 1.8, H-4-py); 8.57 (ddd, 1H, J34 = 7.9, J35 = 1.2, J36 = 0.9, H-3-py); 8.85 (ddd, 1H, J65 = 4.7, J64 = 1.8, J63 = 0.9, H-6-py); 8.93 (s, 1 H, H-2). 13C NMR (151 MHz, DMSO-de): 61.81 (CH2-5 ’); 70.82 (CH-3 ’); 74.28 (CH-2 ’); 85.39 (CH-4 ’); 86.83 (CH-1 ’); 103.63 (CH-5); 115.94 (C-4a); 122.66 (CH-3-py); 125.28 (CH-5-py); 128.57 (CH-6); 137.50 (CH-4-py); 149.89 (CH-6-py); 150.86 (CH-2); 153.07 (C-7a); 153.69 (C-4); 155.97 (C-2-py). IR (KBr): v = 1632, 1577, 1569,

1559, 1453, 1214, 1107, 1100 cm-1. MS FAB, m / z (rel.%): 329 (100) [M + H]. HR MS (FAB): calcd for Ci6Hi7N4O4 [M + H] 329.1250, found 329.1243.

Example 19. 5-Fluoro-4-phenyl-7- (p-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (8a).

[0199] Compound 7a (296 mg, 0.45 mM) is treated with 1M NaOMe / MeOH (135 microL, 0.135 mM) in MeOH (5 mL) for 12 hours at room temperature. The mixture is co-evaporated with silica and exposed to a chromatograph on the silica column (3% MeOH in CHCL) generating the product 8a as a crystalline solid (122 mg, 79%). The compound is crystallized from MeOH / CHCL / hexane in the form of honey-like leaves. 1H NMR (600 MHz, DMSO-cfe): 3.57 (ddd, 1H, Jgem = 12.0, J5b, OH = 5.5, J5b, 4 = 3.9, H-5’b); 3.65 (ddd,

[0196]

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[0198]

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1H, Jgem = 12.0, J5'aOH = 5.5, JSa4 '= 4.1, H-5'a); 3.94 (ddd, 1H, J * 5 = 4.1, 3.9, J * 3 '= 3.2, H-4'); 4.12 (ddd, 1H, Js, 2 = 5.1, J3, oh = 4.9, J3 ', 4' = 3.2, H-3 '); 4.39 (ddd, 1H, J2, oh = 6.3, J2j = 6.1, J2.3 '= 5.1, H-2'); 5.10 (t, 1H, Joh, 5 '=

5.5, OH-5 '); 5.23 (d, 1H, Joh3 '= 4.9, OH-3'); 5.44 (d, 1H, Joh2 '= 6.3, OH-2'); 6.35 (dd, 1H, JX2 = 6.1, Jhf = 1.8, H-1 '); 7.55-7.61 (m, 3H, H-m, p-Ph); 7.97 (m, 2H, H-o-Ph); 7.99 (d, 1H, Jhf = 1.9, H-6); 8.93 (s, 1 H, H-2). 13C NMR (151 MHz, DMSO-de): 61.66 (CH2-5 '); 70.71 (CH-3 '); 74.34 (CH-2 '); 85.51 (CH-4 '); 86.41 (CH-1 '); 106.16 (d, Jcf = 15, C-4a); 110.57 (d, Jcf = 30, CH-6); 128.78 (CH-m-Ph); 129.42 (d, Jcf = 4, CH-o-Ph); 130.67 (CH-p-Ph); 136.98 (C-i-Ph); 141.58 (d, Jcf = 247, C-5); 147.60 (d, Jcf = 3, C-7a); 152.04 (CH-2); 157.00 (d, Jcf = 4, C-4) ;. 19F NMR (470.3 MHz, DMSO-de, ref (C6F6) = -163 ppm): - 161.30. IR (KBr): v = 1632, 1597, 1581, 1567, 14711379,1224,1085,1047cm "\ MSFAB, m / z (rel.%): 346 (100) [M + H], 368 (50) [ M + Na] HR MS (FAB): calcd for C17H17FN3O4 [M + H] 346,1203, found 346,1207.

[0200] Intermediate compound 7a is prepared as follows:

to. 5-Fluoro-4-phenyl-7- (2,3,5-tri-O-benzoyl-p-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (7a). A

purged mixture with 6-chloro-7-fluorodeazapurine 6 riboside argon (329 mg, 0.53 mM), phenylboronic acid (98 mg, 0.80 mM), K2CO3 (150 mg, 1.09 mM) and Pd ( PPh3) 4 (31 mg, 0.027 mM) in toluene (4 ml) is stirred at 100 ° C for 4 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous NH4Cl (sat., 20 mL), the aqueous phase is extracted again with chloroform (2 X 5 milliliters). The organic extracts collected are dried over MgSO4, the volatiles are removed to the ford and the residue is exposed to a silica chromatography (hexanes-AcOEt, 6: 1) generating the product 7a in the form of a colorless foam (325 mg, 93% ). 1H NmR (500 MHz, CDCl3): 4.70 (dd, 1H, Jgem = 12.2, J5'b, 4 '= 3.8, H-5'b); 4.80 (ddd, 1H, J43 = 4.3, J45 '= 3.8, 3.2, H-4'); 4.88 (dd, 1H, Jgem = 12.2, JS4 = 3.2, H-5'a); 6.11 (dd, 1H, Js'2 '= 5.9, Js'4' = 4.3, H-3 '); 6.18 (t, 1H, J2V = J2s = 5.9, H-2 '); 6.86 (dd, 1H, Jr, z = 5.9, Jhf =

1,3, H-1 '); 7.20 (d, 1H, Jhf = 2.4, H-6); 7.36 and 7.42 (2 X m, 2 X 2H, H-m-Bz); 7.47-7.56 (m, 6H, H-m, p-Bz and H-m, p-Ph); 7.59 and 7.60 (2 X m, 2 X 1H, H-p-Bz); 7.95 (m, 2H, H-o-Bz); 7.97 (m, 2H, H-o-Ph); 8.02 and

8.14 (2 X m, 2 X 2H, H-o-Bz); 8.93 (s, 1 H, H-2). 13C NMR (125.7 MHz, CDCl3): 63.75 (CH2-5 '); 71.46 (CH-3 '); 73.76 (CH-2 '); 80.30 (CH-4 '); 85.69 (CH-1 '); 106.53 (d, Jc, f = 15, C-4a); 108.46 (d, Jc, f = 30, CH-6); 128.43 (C - / - Bz); 128.48, 128.50 and 128.54 (CH-m-Bz and CH-m-Ph); 128.72 and 129.33 (C - / - Bz); 129.42 (d, Jcf = 4, CH-o-Ph); 129.68, 129.82 and 129.84 (CH-o-Bz); 130.47 (CH-p-Ph); 133.52 and 133.73 (CH-p-Bz);

136.69 (C-i-Ph); 143.00 (d, Jcf = 253, C-5); 148.13 (d, Jcf = 3, C-7a); 152.39 (CH-2); 158.46 (d, Jcf = 4, C-4); 165.12, 165.41 and 166.13 (CO). 19F NMR (470.3 MHz, CDCl3): -158.37. MS FAB, m / z (rel.%): 658 (100) [M + H]. HR MS (FAB): calcd for C3sH29FN3O7 [M + H] 658.1990, found 658.1991.

Example 20. 5-Fluoro-4- (furan-2-M) -7- (P-D-ribofuransN) -7H-pyrrolo [2,3-d] pmmidma (8b).

[0201]

image35

[0202] Compound 7b (395 mg, 0.61 mM) is treated with 1M NaOMe / MeOH (183 microL, 0.18 mM) in MeOH (5 mL) for 18 hours at room temperature. The mixture is co-evaporated with silica and a chromatography on the silica column (3% MeOH in CHCl3) is exposed, generating the product 8b (160 mg, 78%) as a white solid. Crystallization from MeOH supplies a beige powder. 1H NMR (600 MHz, DMSO-de): 3.56 (ddd, 1H, Jgem = 11.9, J3bOH = 5.5, J3'b4 '= 3.9, H-5'b); 3.64 (ddd, 1H, Jgem = 11.9, J3aOH =

5.5, JSa4 '= 4.1, H-5'a); 3.92 (ddd, 1H, J45 '= 4.1, 3.9, J43' = 3.3, H-4 '); 4.11 (ddd, 1H, JS2 = 5.1, J3oh = 4.9, J34 =

3.3, H-3 '); 4.36 (ddd, 1H, J2oh = 6.3, J2r = 6.1, J23 = 5.1, H-2 '); 5.10 (t, 1H, Joh5 = 5.5, OH-5 '); 5.22 (d, 1H, Joh 3 '= 4.9, OH-3'); 5.43 (d, 1H, Joh2 = 6.3, OH-2 '); 6.31 (dd, 1H, Jr2 = 6.1, Jhf = 1.8, H-1 '); 6.80 (dd, 1H, J43 =

3.5, J45 = 1.7, H-4-furyl); 7.48 (dd, 1H, J34 = 3.5, J33 = 0.8, H-3-furyl); 7.96 (d, 1H, Jhf = 1.9, H-6); 8.08 (dd, 1H, J54 = 1.7, J53 = 0.8, H-5-furyl); 8.81 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-de): 61.64 (CH2-5 '); 70.68 (CH-3 '); 74.34 (CH-2 '); 85.47 (CH-4 '); 86.36 (CH-1'); 102.12 (d, Jcf = 16, C-4a); 110.75 (d, Jcf = 30, CH-6); 113.15 (CH-3-furyl); 114.93 (d, JcF = 6, CH-4-furyl); 141.46 (d, Jcf = 249, C-5); 146.04 (d, Jcf = 4, C-4); 147.02 (CH-5-furyl); 147.80 (d, Jcf = 3, C-7a); 151.12 (C-2-furyl); 151.81 (CH-2). 19F NMR (470.3 MHz, DMSO-de, ref (C6F6) = -163 ppm): -161.79. IR (KBr): v = 1586,1485,1461, 1395, 1249, 1209, 1101, 1046, 1021 cm- ,. MS FAB, m / z (rel.%): 204 (90), 336 (100) [M + H]. HR MS (FAB) calculated for C ^ H ^ N ^ [M + H] 336.0996, found 336.1003.

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[0203] Intermediate compound 7b is presented as follows:

to. 5-Fluoro-4- (furan-2-M) -7- (2,3,5-tri-O-benzoN-p-D-ribofuransM) -7H-pyrrolo [2,3-

d] pyrimidine (7b). A mixture purged with 6-chloro-7-fluorodeazapurine 6 (377 mg, 0.61 mM), 2- (tributilestanyl) furan (270microL, 0.85 mM) and PdCl2 (PPh3) 2 (21 mg, ribosides argon 0.03 mM) in DMF (3 mL) is stirred at 100 ° C for 12 hours. The volatiles are removed to the ford and the residue is evaporated several times with toluene. Silica column chromatography (hexanes-AcOEt, 20: 1 ^ 10: 1) generates the product 7b in the form of a yellowish foam (395 mg, 100%). 1H NMR (600 MHz, CDCla): 4.69 (dd, 1H, Jgem = 12.2, JSb4 = 3.7, H-5'b); 4.80 (ddd, 1H, J4'3 '= 4.1, Jas = 3.7, 3.1, H-4'); 4.88 (dd, 1H, Jgem = 12.2, J5'a, 4 '= 3.1, H-5'a); 6.09 (dd, 1H, Js, 2 = 5.9, JSA = 4.1, H-3 '); 6.14 (t, 1H, J2? = J2, r = 5.9, H-2 '); 6.63 (dd, 1H, J43 = 3.5, J45 = 1.7, H-4-furyl); 6.84 (dd, 1H, Jr2 = 5.9, Jhf = 1.3, H-1 '); 7.199 (d, 1H, Jhf = 2.4 H-6); 7.36 and 7.42 (2 X m, 2 X 2H, H-m-Bz); 7.50 (dd, 1H, J34 = 3.5, J35 = 0.7, H-3- furyl); 7.51 (m, 2H, H-m-Bz); 7.54, 7.60 and 7.62 (3 X m, 3 X 1H, H-p-Bz); 7.71 (dd, 1H, J54 = 1.7, J53 = 0.7, H-5-furyl); 7.93, 8.02 and 8.15 (3 X m, 3 X 2H, H-o-Bz); 8.85 (s, 1H, H-2). 13C NMR (151 MHz, CDCla): 63.73 (CH2-5 '); 71.40 (CH-3 '); 73.69 (CH-2 '); 80.26 (CH-4 '); 85.41 (CH-1 '); 103.47 (d, Jcf = 16, C-4a); 108.46 (d, Jcf = 31, CH-6); 112.66 (CH-4-furyl); 115.68 (d, Jcf = 11, CH-3- furyl); 128.30 (C - / - Bz); 128.48 and 128.54 (CH-m-Bz); 128.60 (C - / - Bz); 128.72 (CH-m-Bz); 129.23 (C - / - Bz); 129.66, 129.81 and 129.82 (CH-o-Bz); 133.56 and 133.76 (CH-p-Bz); 142.79 (d, Jcf = 253, C-5); 145.84 (CH-5-furyl); 147.07 (d, Jc, f = 4, C-4); 148.16 (d, Jc, f = 3, C-7a); 150.45 (C-2-furyl); 152.25 (CH-2); 165.11, 165.42 and 166.15 (CO). 19F NMR (470.3 MHz, CDCh): -159.30. MS FAB, m / z (rel.%): 648 (100) [M + H]. HR MS (FAB): calcd for C36H27FN3O8 [M + H] 648.1778, found 648.1775.

Example 21. 5-Fluoro-7- (P-D-ribofuransN) -4- (thiophen-2-N) -7H-pyrrolo [2,3-d] pyrimidma (8c).

[0204]

image36

[0205] Compound 7c (145 mg, 0.22 mM) is treated with 1 M NaOMe / MeOH (40 microL, 0.04 mM) in MeOH (4 mL) for 12 hours at room temperature. The mixture is co-evaporated with silica and exposed to chromatography on the silica column (2.5% MeOH in CHCl3) generating the product 8c (57 mg, 74%) as a solid similar to the lemon. Crystallization from MeOH / AcOEt / hexane generated a yellowish powder. 1H NMR (600 MHz, DMSO-de): 3.56 (ddd, 1H, Jgem = 11.9, JSbOH = 5.4, JSb4 '= 4.0, H-5'b); 3.65 (ddd, 1H, Jgem = 11.9, J5a, OH = 5.4, JSa, 4 '= 4.1, H-5'a); 3.93 (ddd, 1H, J4.5 = 4.1, 4.0, J *, 3 '= 3.1, H-4'); 4.11 (ddd, 1H, J3oh = 4. 9, J3'2 = 4.8, J3'4 '= 3.1, H-3'); 4.36 (ddd, 1H, J2oh = 6.3, J2r = 6.0, J2s = 4.8, H-2 '); 5.10 (t, 1H, Joh5 '=

5.4, OH-5 '); 5.22 (d, 1H, Joh3 = 4.9, OH-3 '); 5.44 (d, 1H, Joh2 = 6.3, OH-2 '); 6.32 (dd, 1H, Jr2 = 6.0, Jhf = 1.9, H-1 '); 7.31 (dd, 1H, J45 = 5.0, J43 = 3.8, H-4-thienyl); 7.90 (dd, 1H, J54 = 5.0, J53 = 1.1, H-5-thienyl); 8.01 (d, 1H, Jhf = 1.8, H-6); 8.07 (dd, 1H, J3 4 = 3.8, J35 = 1.1, H-3-thienyl); 8.78 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-de): 61.61 (CH2-5 '); 70.64 (CH-3 '); 74.37 (CH-2 '); 85.48 (CH-4 '); 86.46 (CH-1 '); 102.44 (d, Jcf = 15, C-4a); 110.70 (d, Jcf = 31, CH-6); 129.39 (d, Jcf = 2, CH-4-thienyl); 130.31 (d, Jcf = 16, CH-3-thienyl); 131.99 (CH-5-thienyl); 141.53 (d, JcF = 246, C-5); 141.98 (C-2-thienyl); 147.73 (d, Jcf = 3, C-7a); 150.25 (d, Jcf = 4, C-4); 151.71 (CH-2). 19FNMR (470.3MHz, DMSO-de, ref (C6F6) = - 163ppm): -160.86. IR (KBr): v = 1633, 1590, 1565, 1458, 1428, 1102, 1056cm '\ MSFAB, m / z (rel.%): 220 (100), 352 (20) [M + H]. HR MS (FAB): calcd for C15H15FN3O4S [M + H] 352.0767, found 352.0754.

[0206] Intermediate compound 7c is prepared as follows:

to. 5-Fluoro-4- (thiophen-2-N) -7- (2,3,5-tri-O-benzoN-p-D-ribofuransN) -7H-pyrrolo [2,3-

d] pyrimidine (7c). A purged mixture of 6-chloro-7-fluorodeazapurine 6 riboside argon (205 mg, 0.33 mM), 2- (tributilestanyl) thiophene (116 mL, 0.365 mM) and PdCh (PPh3) 2 (12 mg, 0.017 mM) in DMF (3 mL) is stirred at 100 ° C for 3 hours. The volatiles are removed to the ford and the residue is co-evaporated several times with toluene. Silica column chromatography (hexanes-AcOEt, 20: 1 1 ^ 10: 1) generates the product 7c in the form of a yellowish foam (164 mg, 74%). 1H NMR (600 MHz, CDCh):

4.69 (dd, 1H, Jgem = 12.2, JSb4 = 3.7, H-5'b); 4.80 (ddd, 1H, J * 3 '= 4.1, J4 5' = 3.7, 3.0, H-4 '); 4.88 (dd, 1H, Jgem = 12.2, J5a4 '= 3.0, H-5'a); 6.09 (dd, 1H, J32 = 5.9, J3 4 '= 4.1, H-3'); 6.14 (dd, 1H, J2r = 6.1, J23 = 5.9, H-2 '); 6.86 (dd, 1H, JX2 = 6.1, Jhf = 1.4, H-1 '); 7.199 (d, 1H, Jh, f = 2.2, H-6); 7.202 (dd, 1H, JA, 5 = 5.0, J43 = 3.8, H-4-thienyl); 7.36, 7.42 and 7.51 (3 X m, 3 X 2H, H-m-Bz); 7.54 (m, 1H, H-p-Bz); 7.58 (dd,

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1H, J54 = 5.0, J53 = 1.1, H-5-thienyl); 7.59 and 7.63 (2 x m, 2 x 1H, H-p-Bz); 7.94 and 8.02 (2 X m, 2 X 2H, H- or -Bz); 8.10 (dd, 1H, J3.4 = 3.9, J3.5 = 1.1, H-3 -thienyl); 8.15 (m, 2H, H-o-Bz); 8.79 (s, 1H, H-2). 13C NMR (151 MHz, CDCh): 63.77 (CH2-5 '); 71.43 (CH-3'); 73.67 (CH-2 '); 80.30 (CH-4 '); 85.32 (CH-1 '); 103.85 (d, Jcf = 15, C-4a); 108.23 (d, JoF = 32, CH-6); 128.30 (C - / - Bz); 128.40 and 128.54 (CH-m-Bz); 128.60 (C - / - Bz); 128.72 (CH-m-Bz); 128.82 (d, JcF = 2, CH-4-thienyl); 129.23 (C - / - Bz); 129.66, 129.81 and 129.82 (CH-o-Bz); 130.63 (d, JcF = 17, CH-3-thienyl); 130.84 (CH-5-thienyl); 133.57 and 133.75 (CH-p-Bz); 141.92 (C-2-thienyl); 142.93 (d, JcF = 251, C-5); 148.96 (d, JcF = 3, C-7a); 152.94 (d, Jcf = 4, C-4); 152.08 (CH-2); 165.10, 165.41 and 166.13 (CO) .19FNMR (470.3MHz, CDCl3): - 158.00.MSFAB, Jz (rel.%): 664 (100) [M + H]. HR MS (FAB): calcd for C36H27FN3O7S [M + H] 664.1555, found 664.1542.

Example 22. 5-Fluoro-4- (pyrrole-2-M) -7- (P-D-ribofuransN) -7H-pyrrolo [2,3-d] pmmidma (8d).

[0207]

image37

[0208] Compound 7d (166 mg, 0.257 mM) is treated with 1 M NaOMe / MeOH (77 microL, 0.077 mM) in MeOH (4 mL) for 12 hours at room temperature. The mixture is co-evaporated with silica and a chromatography is performed on the silica column (4% MeOH in CHCh) generating the product 8d (76 mg, 89%) as a beige solid. The compound crystallizes from MeOH. 1H NmR (500 MHz, DMsOd6): 3.56 (ddd, 1H, Jgem = 12.0, JsbOH = 5.5, JSb4 '= 4.0, H-5'b); 3.64 (ddd, 1H, Jgem = 12.0, JSa oh = 5.4, J & a4 '= 4.0, H-5'a); 3.91 (td, 1H, J4 ', 5' = 4.0, J *, 3 '= 3.3, H-4'); 4.11 (ddd, 1H, Js, 2 = 5.1, J3, oh = 4.9, J34 = 3.3, H-3 '); 4.35 (ddd, 1H, J2'oh = 6.2, J2'1 = 6.1, J23 '= 5.1, H-2'); 5.08 (dd, 1H, Joh5 '= 5.5, 5.4, OH-5'); 5.17 (d, 1H, J0H3 '= 4.9, OH-3'); 5.38 (d, 1H, J0H2 '= 6.2, OH-2'); 6.27 (dd, 1H, Jrz = 6.1, Jhf = 1.9, H-1 '); 6.30 (ddd, 1H, J43 = 3.7, J45 = 2.5, J4nh = 2.3, H-4-pyrr); 7.08 (ddd, 1H, J5NH = 2.9, J54 = 2.5, J53 = 1.3, H-5-pyrr); 7.17 (ddt, 1H, J34 = 3.7, J3nh =

2.5, J3.5 = JH, F = 1.3, H-3-pyrr); 7.83 (d, 1H, Jh, f = 1.9, H-6); 8.70 (s, 1 H, H-2); 11.85 (bs, 1H, NH). 13C NMR (125.7 MHz, DMSO-cfe): 61.67 (CH2-5 '); 70.65 (CH-3 '); 74.23 (CH-2 '); 85.35 (CH-4 '); 86.38 (CH-1 '); 101.32 (d, Jc, f = 15, C-4a); 109.18 (d, JcF = 31, CH-6); 110.86 (d, Jcf = 2, CH-4-pyrr); 114.06 (d, Jcf = 18, CH-3-pyrr); 123.82 (CH-5- pyrr); 128.30 (C-2-pyrr); 141.81 (d, Jcf = 246, C-5); 147.42 (d, Jcf = 3, C-7a); 148.56 (d, Jcf = 4, C-4); 151.65 (CH-2) .19FNMR (470.3MHz, DMSOd6, ref (C6F6) = -163 ppm): -161.47. MS FAB, mlz (rel.%): 335 (100) [M + H]. HRMS (FAB): calcd for C15H16FN4O4 [M + H] 335.1156, found 335.1161. Anal. Calcd for C15H15FN4O4- and 2H2O: C, 52.48; H, 4.70; N, 16.32. Found: C, 52.66; H, 4.53; N, 16.05.

[0209] Intermediate compound 7d is prepared as follows:

to. 5-Fluoro-4- (pyrrole-2-N) -7- (2,3,5-tri-O-benzoM-p-D-NbofuransM) -7H-pyrrolo [2,3-

d] pyrimidine (7d). Pyrrole, in the form of drops, (242 pl, 3.5 mM) was added to a suspension of NaH (55% in mineral oil, 153 mg, 3.5 mM) in THF (4 ml) and the mixture was stirred for 30 minutes at room temperature, followed by the addition of a solution of ZnCh (1 M sol in THF, 3.8 ml, 3.8 mM). The resulting spice solution is stirred for an additional 2 hours and then transferred by means of a cannula to an argon purged flask with 6-chloro-7-fluorodeazapurine 6 ribosides (431 mg, 0.7 mM), Pd (PPh3) 4 (40 mg, 0.035 mM) and the reaction mixture is stirred at 90 ° C for 12 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous EDTA (sat., 20 ml). The aqueous layer is reextracted with chloroform (2 X 5 milliliters). The organic extracts collected are dried over MgSO4, evaporated and a silica chromatography (hexanes-AcOEt, 5: 1) is exposed, generating the product 7d (188 mg, 42%) in the form of a yellowish foam. 1H NMR (500 MHz, cDch): 4.68 (dd, 1H, Jgem = 12.2, J5b4 '= 3.8, H-5'b); 4.78 (ddd, 1H, J43 = 4.3, J4 5 '= 3.8, 3.2, H-4'); 4.86 (dd, 1H, Jgem =

12.2, JSa4 '= 3.2, H-5'a); 6.09 (dd, 1H, J32 '= 5.8, JS4 = 4.3, H-3'); 6.15 (t, 1H, Jzr = Jz3 '= 5.8, H-2'); 6.39 (dt, 1H, J43 = 3.8, J45 = J4nh = 2.6, H-4-pyrrole); 6.80 (dd, 1H, Jrz = 5.8, Jhf = 1.5, H-1 '); 7.04 (td, 1H, J54 = J5 nh = 2.6, J53 = 1.3, H-5-pyrrole); 7.11 (d, 1H, Jhf = 2.4, H-6); 7.45 (ddd, 1H, J3 4 = 3.8, J3 nh = 2.4, J35 =

1,3, H-3-pyrrole); 7.35, 7.40 and 7.49 (3 x m, 3 x 2H, H-m-Bz); 7.53, 7.59 and 7.60 (3 X m, 3 X 1H, H-p-Bz); 7.94, 8.00 and 8.14 (3 X m, 3 X 2H, H-o-Bz); 8.66 (s, 1 H, H-2); 9.97 (bs, 1H NH). 13C NMR (125.7 MHz, CDCh): 63.79 (CH2-5 '); 71.47 (CH-3 '); 73.74 (CH-2 '); 80.19 (CH-4 '); 85.51 (CH-1 '); 102.76 (d, Jcf = 16, C-4a); 107.26 (d, Jcf = 31, CH-6); 111.65 (Jcf = 3, CH-4-pyrrole); 114.64 (Jcf = 17, CH-3-pyrrole); 123.38 (CH-5-pyrrole); 128.50 (CH-m-Bz); 128.50 (C-2-pyrrole); 128.52 (CH-m-Bz); 128.65 (C - / - Bz); 128.69 (CH-m-Bz); 128.75 and 129.37 (C - / - Tol); 129.70, 129.83 and 129.85 (CH-o-Bz); 133.49 and 133.68 (CH-p-Tol); 143.24 (d, Jcf = 251, C-5); 148.05 (d, Jcf = 4, C-7a); 148.82 (d, Jcf = 4, C-4); 152.05 (CH-2); 165.11, 165.41 and

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166.15 (CO). 19F NMR (470.3 MHz, CDCI3, ref (C6F6) = -163 ppm): -158.88. MS FAB, m / z (rel.%): 203 (100), 279 (100), 647 (75) [M + H]. HR MS (FAB): calcd for C36H28FN4O7 [M + H] 647.1942, found 647.1915.

Example 23. 5-Fluoro-4- (furan-3-M) -7- (P-D-ribofuransN) -7H-pyrrolo [2,3-d] pmmidma (8e).

[0210]

image38

[0211] Compound 7e (132 mg, 0.20 mM) is treated with 1 M of 1M NaOMe / MeOH (40 mL, 0.04 mM) in MeOH

(4 mL) for 12 hours at room temperature. The mixture is co-evaporated with silica and exposed to a silica column chromatography (3% MeOH in CHCh) generating the product 8e (53 mg, 78%) as a colorless solid. Crystallization from MeOH / AcOEt / hexane facilitates a white powder. 1H NMR (600 MHz, DMSO-d6): 3.56 (ddd, 1H, Jgem = 11.9, Js’b oh = 5.5, J5W = 4.0, H-5'b); 3.64 (ddd, 1H, Jgem =

11.9, J5aOH = 5.5, J5'a4 '= 4.2, H-5'a); 3.92 (ddd, 1H, J4'5 '= 4.2, 4.0, J * 3' = 3.1, H-4 '); 4.11 (ddd, 1H, J32 '= 5.1, J3, OH = 4.9, Js', 4 '= 3.1, H-3'); 4.36 (ddd, 1H, J2, oh = 6.3, J2, r = 6.1, J2, s = 5.1, H-2 '); 5.09 (t, 1H, Joh, 5 '= 5.5, OH-5'); 5.22 (d, 1H, Joh3 '= 4.9, OH-3'); 5.43 (d, 1H, Joh2 '= 6.3, OH-2'); 6.31 (dd, 1H, JX2 = 6.1, Jhf = 1.9, H-1 '); 7.17 (dd, 1H, J45 = 1.8, J42 = 0.7, H-4-furyl); 7.90 (dd, 1H, J3A = 1.8, J52 = 1.6, H-5-furyl); 7.96 (d, 1H, Jhf =

1.8, H-6); 8.48 (dt, 1H, J25 = 1.6, J24 = Jhf = 0.7, H-2-furyl); 8.82 (s, 1H, 'H-2). 13C NMR (151 MHz, DMSO-ds): 61.64 (CH2-5 '); 70.67 (CH-3 '); 74.32 (CH-2 '); 85.46 (CH-4 '); 86.39 (CH-1 '); 104.03 (d, Jc, f = 15, C-4a); 109.97 (d, Jcf = 6, CH-4-furyl); 110.27 (d, Jcf = 30, CH-6); 124.52 (C-3-furyl); 141.53 (d, Jcf = 246, C-5); 144.91 (CH-5-furyl); 145.49 (d, Jcf = 13, CH-2-furyl); 147.43 (d, Jcf

= 3, C-7a); 149.68 (d, Jcf = 4, C-4); 152.02 (CH-2). 19F NMR (470.3 MHz, DMSO-d6, ref (C6F6) = -163 ppm): - 163.20.IR (KBr): v = 1630, 1589, 1463, 1250, 1220, 1161, 1083, 1052 cm -. MS FAB, m / z (rel.%): 204 (100), 336 (25) [M + H] .HR MS (FAB): calcd for C15H15FN3O5 [M + H] 336.0996, found 336.0991.

[0212] Intermediate compound 7e is prepared as follows:

to. 5-Fluoro-4- (furan-3-M) -7- (2,3,5-tri-O-benzoN-P-D-ribofuransM) -7H-pyrrolo [2,3-

d] pyrimidine (7e). A mixture purged with argon of 6-chloro-7- fluorodeazapurine 6 protected ribosides (216 mg, 0.35 mM), furan-3-boronic acid (49 mg, 0.44 mM), K2CO3 (72 mg, 0, 52 mM) and Pd (PPh3) 4 (20 mg, 0.017 mM) in toluene (2 mL) is stirred 100 ° C for 10 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous NH4Cl (sat., 20 mL), the aqueous phase is extracted again with chloroform (2 X 5 milliliters). The collected organic extracts are dried over MgSO4, the volatiles are removed to the ford and the residue is exposed to silica chromatography (hexanes-AcOEt, 6: 1) generating the product 7e in the form of a colorless foam (151 mg, 66%) . 1H NMR (600 MHz, CDCl3): 4.68 (dd, 1H, Jgem = 12.2, J3bx = 3.7, H-5'b); 4.80 (ddd, 1H, J43 '= 4.1, J45' = 3.7, 3.0 H- 4 '); 4.88 (dd, 1H, Jgem = 12.1, J & a4 '= 3.0, H-5'a); 6.09 (dd, 1H, JS2 = 5.8, J34 '' = 4.1, H-3 '); 6.14 (dd, 1H, J21 '= 6.1, J23' = 5.8, H-2 '); 6.84 (dd, 1H, JV2 = 6.1, Jhf = 1.3, H-1 '); 7.17 (d, 1H, Jhf = 2.2, H-6); 7.18 (dd, 1H, J45 = 1.8, Jhf = 0.7, H-4-furyl); 7.36, 7.42 and 7.51 (3 X m, 3 X 2H, H-m-Bz); 7.54 (dd, 1H, J54 =

1.8, J52 = 1.6, H-5-furyl); 7.54, 7.60 and 7.63 (3 X m, 3 X 1H, H-p-Bz); 7.93, 8.02 and 8.15 (3 X m, 3 X 2H, H- or-Bz); 8.32 (dd, 1H, J25 = 1.6, Jhf = 0.7, H-2-furyl); 8.83 (s, 1H, H-2). 13C NMR (151 MHz, CDCh): 63.76 (CH2-5 '); 71.42 (CH-3 '); 73.64 (CH-2 '); 80.25 (CH-4 '); 85.34 (CH-1 '); 105.29 (d, Jcf = 15, C-4a); 108.01 (d, Jcf = 31, CH-6); 109.75 (d, Jcf = 6, CH-4-furyl); 124.39 (C-3-furyl); 128.30 (C - / - Bz); 128.47 and 128.54 (CH-m-Bz); 128.60 (C - / - Bz); 128.72 (CH-m-Bz); 129.23 (C - / - Bz); 129.66, 129.81 and 129.82 (CH- or-Bz); 133.57 and 133.76 (CH-p-Bz); 142.88 (d, Jcf = 251, C-5); 143.76 (CH-5-furyl); 145.53 (d, Jcf = 15, CH-2-furyl); 147.95 (d, JcF = 3, C-7a); 150.99 (d, Jcf = 4, C-4); 152.38 (CH-2); 165.11, 165.42 and 166.14 (CO). 19F NMR (470.3 MHz, CDCh): - 160.62. MS FAB, m / z (rel.%): 648 (100) [M + H]. HR MS (FAB): calcd for C36H27FN3O8 [M + H] 648.1782, found 648.1807.

Example 24. 5-Fluoro-7- (P-D-ribofuransN) -4- (thiophen-3-N) -7H-pyrrolo [2,3-d] pyrimidma (8f).

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image39

[0214] Compound 7f (136 mg, 0.20 mM) is treated with 1M NaOMe / MeOH (40 microliters, 0.04 microM) in

MeOH (4 mL) for 12 hours at room temperature. The mixture is co-evaporated with silica and exposed to a chromatograph on the silica column (3% MeOH in CHCL) generating the product 8f (58 mg, 81%) as a colorless solid. Crystallization from MeOH / AcOEt / hexane facilitated a white powder. 1H NMR (600 MHz, DMSO-de): 3.56 (ddd, 1H, Jgem = 11.9, J5bOH = 5.5, J5’b4 ’= 4.0, H-5’b); 3.64 (ddd, 1H, Jgem = 11.9, JsaOH = 5.5, J5'a4 '= 4.1, H-5’a); 3.93 (ddd, 1H, J4> 5> = 4,1,4,0, J4 "3" = 3,3, H-4 '); 4.11 (ddd, 1H, J3z = 5.1, J30h =

4.9, J3 "4" = 3.3, H-3 "); 4.37 (ddd, 1H, J20h = 6.3, J? V = 6.1, 3 = 5.1, H-2 ’); 5.10 (t, 1H, J0H5 = 5.5, OH-5 ’); 5.22

(d, 1H, Joh.s = 4.9, OH-3 ’); 5.43 (d, 1H, J0H, 2 ’= 6.3, OH-2’); 6.33 (dd, 1H, Jv, z = 6.1, Jh, f = 1.9, H-1 ’); 7.74 (dd, 1H, J54 = 5.1, J52 = 2.9, H-5-thienyl); 7.83 (ddd, 1H, J45 = 5.0, J42 = 1.4, Jhf = 0.8, H-4-thienyl); 7.98 (d, 1H, JHF = 1.8, H-6); 8.36 (ddd, 1H, J25 = 2.9, J24 = 1.4, Jhf = 0.6, H-2-thienyl); 8.85 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-cfe): 61.65 (CH2-5 ’); 70.68 (CH-3 ’); 74.33 (CH-2 ’); 85.47 (CH-4 ’); 86.38 (CH-1 ’); 104.16 (d, f = 15, C-4a); 110.43 (d, Jc, F = 31, CH-6); 127.31 (CH-5-thienyl); 128.03 (d, Jc, f = 6, CH-4-thienyl); 129.56 (d, Jc, f = 11, CH-2- thienyl); 139.09 (C-3-thien); 141.58 (d, Jc, f = 247, C-5); 147.73 (d, Jc, f = 3, C-7a); 151.74 (d, Jc, f = 4, C-4); 151.94 (CH-2). 19F NMR (470.3 MHz, DMSOcfe, ref (C6F6) = -163 ppm): -161.15. IR (KBr): v = 1631, 1571, 1462, 1110, 1079,1049cm'1.MSFAB, m / z (rel.%): 220 (100), 352 (60) [M + H], HR MS ( FAB): calcd for C15H15FN3O4S [M + H] 352.0767, found 352.0770.

[0215] Intermediate compound 7f is prepared as follows:

to. 5-Fluoro-4- (thiophen-3-yl) -7- (2,3,5-tri-0-benzoyl-p-D-ribofuranosyl) -7H-pyrrolo [2,3-

d] pyrimidine (7f). A mixture purged with argon of 6-chloro-7- fluorodeazapurine 6 protected ribosides (216 mg, 0.35 mM), thiophene-3-boronic acid (56 mg, 0.44 mM), K2C03 (72 mg, 0, 52 mM) and Pd (PPh3) 4 (20 mg, 0.017 mM) in toluene (2 mL) is stirred at 100 ° C for 16 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous NH4CI (sat., 20 mL), the aqueous phase is reextracted with chloroform (2X5 milliliters). The organic extracts collected are dried over MgSO4, the volatiles are removed in vacuo and the residues are exposed to a silica chromatograph (hexanes-AcOEt, 6: 1) generating the product 7f in the form of a yellowish foam (155 mg, 67% ). 1H NMR (500 MHz, CDCI3): 4.69 (dd, 1 H, Jgem = 12.1, ^ 5b, 4 = 3.7, H-5'b); 4.79 (ddd, 1H, J4, 3 = 4.2, J4 ', 5' = 3.7, 3.1, H-4 '); 4.88 (dd, 1H, Jgem = 12.1, J5a4 ’= 3.1, H-5’a); 6.10 (dd, 1H, J3Z = 6.0, J3 «4- =

4.2, H-3 ’); 6.16 (dd, 1H, J2.3 = 6.0, J2, r = 5.9, H-2 ’); 6.85 (dd, 1H, Jr, z = 5.9, Jh, f = 1.4, H-1 ’); 7.19 (d, 1H, Jh, f = 2.3, H-6); 7.36 (m, 2H, H-m-Bz); 7.42 (dd, 1H, J5.4 = 5.1, J5) 2 = 3.0, H-5-thienyl); 7.42 and 7.50 (2 X m, 2 x 2H, Hm-Bz); 7.54, 7.59 and 7.62 (3 X m, 3 X 1H, H-p-Bz); 7.87 (ddd, 1H, J4 5 = 5.1, J42 = 1.2, JH f = 0.8, H-4-thienyl); 7.94, 8.01 and 8.15 (3 X m , 3 X 2H, Ho-Bz); 8.23 (dd, 1H, J2.5 = 3.0, J2.4 = 1.2, H-2-thienyl); 8.86 (s, 1 H, H-2) .13 CNMR (125.7 MHz, CDCI3): 63.77 (CH2-5 ’); 71.47 (CH-3 ’); 73.74 (CH-2 ’); 80.30 (CH-4 ’); 85.53 (CH-1’); 105.49 (d, Jc f = 15, C-4a); 108.23 (d, Jcf = 31, CH-6); 125.89 (CH-5-thienyl); 128.08 (d, Jcf = 6, CH-4-thienyl); 128.41 (C / -Bz); 128.47, 128.54 and 128.71 (CH-m-Bz); 129.13 (d, Jcf = 11, CH-2- thienyl); 129.33 (C - / - Bz); 129.69, 129.83 and 129.84 (CH-o-Bz); 133.53 and 133.73 (CH-p-Bz); 139.02 (C-3- thienyl); 142.97 (d, Jc, f = 251, C-5); 148.31 (d, Jc, f = 3, C-7a); 152.35 (CH-2); 152.94 (d, Jc, f = 4, C-4); 165.11, 165.41 and 166.14 (CO). 19F NMR (470.3 MHz, CDCI3): -154.62. MS FAB, m / z (rel.%): 664 (100) [M + H]. HR MS (FAB): calcd for C36H27FN307S [M + H] 664.1554, found 664.1552.

Example 25. 5-Fluoro-7- (p-D-ribofuranosyl) -4- (thiazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine (8g).

[0216]

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[0217] Compound 7g (317 mg, 0.48 mM) is treated with 1 M NaOMe / MeOH (143 microliters, 0.14 mM) in

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MeOH (5 mL) for 12 hours at room temperature. The mixture is co-evaporated with silica and a chromatograph is exposed in the silica column (3% MeOH in CHCh) generating the product 8g as a yellow solid (115 mg, 68%). The compound is crystallized from MeOH in the form of yellow crystals. 1H NMR (600 MHz, DMSO-d6): 3.57 (ddd, 1H, Jgem = 11.9, J? BOH = 5.4, J & b, 4 '= 3.9, H-5'b); 3.65 (ddd, 1H, Jgem =

11.9, J5'aOH = 5.4, J5'a4 '= 4.0, H-5'a); 3.93 (ddd, 1H, Jxs = 4.0, 3.9, J4 3 '= 3.4, H-4'); 4.12 (td, 1H, JS2 = J30H =

4.9, Js # = 3.4, H-3 '); 4.37 (ddd, 1H, J2oh = 6.2, J2X = 6.1, J23 '= 4.9, H-2'); 5.11 (t, 1H, Joh, 5 '= 5.4, OH-5'); 5.23 (d, 1H, Joh3 '= 4.9, OH-3'); 5.46 (d, 1H, Joh2 '= 6.2, OH-2'); 6.34 (dd, 1H, JX2 = 6.1, Jhf = 1.7, H-1 '); 8.05 (d, 1H, Jhf = 2.2, H-6); 8.08 (d, 1H, J54 = 3.1, H-5-thiazolyl); 8.20 (d, 1H, J45 = 3.1, H-4-thiazolyl); 8.90 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-cfe): 61.58 (CH2-5 '); 70.65 (CH-3 '); 74.43 (CH-2 '); 85.54 (CH-4 '); 86.49 (CH-1 '); 103.01 (d, Jc, f = 16, C-4a); 112.27 (d, Jc, f = 29, CH-6); 125.00 (CH-5-thiazolyl); 141.60 (d, Jc, f = 252, C-5); 145.80 (CH-4-thiazolyl); 148.28 (d, JcF = 3, C-7a); 148.87 (d, Jcf = 5, C-4); 151.49 (CH-2); 166.49 (d, Jcf = 3, C-2-thiazolyl). 19F NMR (470.3MHz, DMSO-d6, ref (C6F6) = -163 ppm): -157.84. IR (KBr): v = 1632, 1589, 1565, 1454, 1415, 1221, 1108,1018cm '\ MSFAB, m / z (rel.%): 221 (60), 353 (100) [M + H]. HR MS (FAB): calcd for C14H14FN4O4S [M + H] 353.0720, found 353.0713.

[0218] Intermediate compound 7g is prepared as follows:

to. 5-Fluoro-4- (thiazol-2-yl) -7- (2,3,5-tri-O-benzoyl-p-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (7g).

A mixture purged with 6-chloro-7-fluorodeazapurine 6 riboside argon (376 mg, 0.61 mM), 2- (tributilestanyl) thiazole (361 mg, 0.96 mM) and PdCh (PPh3) 2 (22 mg , 0.03 mM) in DmF (3 mL) is stirred at 100 ° C for 2 hours. The volatiles are removed to the ford and the residue is co-evaporated several times with toluene. Silica column chromatography (hexanes-AcOEt, 15: 1 ^ 6: 1) generates the product 7g in the form of a yellow foam (347 mg, 86%). 1H NMR (600 MHz, CDCh): 4.70 (dd, 1H, Jgem = 12.2, Jsb4 '= 3.7, H-5'b); 4.81 (ddd, 1H, Jxs = 4.1, J4 5 '= 3.7, 3.0, H-4'); 4.89 (dd, 1H, Jgem = 12.2, J & a4 '= 3.0, H-5'a); 6.10 (dd, 1H, JS2 = 5.8, Js # = 4.1, H-3 '); 6.16 (dd, 1H, Jzr = 6.0, J23 '= 5.8, H-2'); 6.86 (dd, 1H, Jrz = 6.0, Jhf = 1.2, H-1 '); 7.29 (d, 1H, Jhf = 2.7 H-6); 7.36, 7.42 and 7.50 (3 3 m, 3 3 2H, H-m-Bz); 7.54 and 7.59 (2 3 m, 2 3 1H, H-p-Bz); 7.59 (d, 1H, J5A = 3.1, H-5-thiazolyl); 7.61 (m, 1H, H-p-Bz); 7.93 and 8.02 (2 X m, 2 X 2H, H-o-Bz); 8.13 (d, 1H, J45 = 3.1, H-4-thiazolyl); 8.15 (m, 2H, H-o-Bz); 8.86 (s, 1H, H-2). 13C NMR (151 MHz, CDCl3): 63.69 (CH2-5 '); 16, C-4a); 110.17 (d, Jcf = 30, CH-6); 123.27 (CH-5-thiazolyl); 128.29 (Ci-71.42 (CH-3 '); 73.75 (CH-2'); 80.37 (CH-4 '); 85.61 (CH-1'); 104.51 ( d, Jcf = Bz); 128.46 and 128.53 (CH-m-Bz); 128.59 (C - / - Bz); 128.73 (CH-m-Bz); 129.18 (Ci- Bz); 129.63, 129.79 and 129.80 (CH-o-Bz); 133.57 and133.74 (CH-p-Bz); 142.94 (d, Jcf = 257, C-5); 145.48 (CH-4-thiazolyl); 148.71 (d, Jcf = 3, C-7a); 149.94 (d, JcF = 5, C-4); 151.69 (CH-2); 165.03, 165.38 and 166.14 (CO); 166.65 (d, Jcf = 3, C-2-thiazolyl) .19FNMR (470.3MHz, CDCl3): - 155.97.MSFAB, m / z (rel.%): 665 (100) [M + H] HRMS (FAB): calcd for C35H26FN4O7S [M + H] 665,1506, found 665.1531.

Example 26. 5-Fluoro-4- (1H-imidazol-4-M) -7- (P-D-nbofuranesN) -7H-pyrrolo [2,3-d] pmmidma (8h).

[0219]

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[0220] Compound 7h (230 mg, 0.26 mM) in pyridine (2 ml) is treated with 1 M NaOMe / MeOH (800 microliters, 0.8 mM) for one hour at room temperature. The resulting solution is desalinated by Dowex 50 (a form of pyridinium) and the volatiles are evaporated in vacuo and the residue is co-evaporated several times with MeOH / toluene and then treated with 90% aqueous TFA (1 milliliter) for 18 hours at room temperature. The volatiles are removed to the ford and the residue is co-evaporated several times with MeOH. Reverse phase chromatography generates nucleoside 8h (61 mg, 70%) in the form of a white solid that is difficult to solubilize. 1H NMR (500 MHz, DMSO-d6 + DCl): 3.54 (dd, 1H, Jgem = 12.0, J & b4 '= 3.9, H-5'b); 3.61 (dd, 1H, Jgem = 12.0, J5'a4 '= 4.0, H-5'a); 3.93 (ddd, 1H, J4.5 = 4.0, 3.9, Jxs = 3.2, H-4 '); 4.11 (dd, 1H, J32 = 5.1, J34 '= 3.2, H-3'); 4.35 (dd, 1H, J2X = 6.1, J2S = 5.1, H-2 '); 6.30 (dd, 1H, Jr2 = 6.1, Jhf = 1.9, H-1 '); 8.08 (d, 1H, Jhf = 1.9, H-6); 8.24 (d, 1H, J52 = 1,2, H-5-imidazole); 8.94 (s, 1 H, H-2); 9.30 (d, 1H, J25 = 1,2, H-2-imidazole). 13C NMR (125.7 MHz, DMSO-d6 + DCl): 61.67 (CH2-5 '); 70.79 (CH-3 '); 74.65 (CH-2 '); 85.85 (CH-4 '); 86.84 (CH-1 '); 103.75 (d, Jcf = 16, C-4a); 112.11 (d, Jcf = 30, CH-6); 121.87 (d, Jcf = 18, CH-5-imidazole); 129.59 (C-4- imidazole); 137.01 (CH-2-imidazole); 141.26 (d, Jcf = 247, C-5); 143.82 (d, Jcf = 4, C-4); 147.63 (d, Jcf = 3, C-7a); 151.59 (CH-2). 19F NMR (470.3 MHz, DMSO-d6 + DCl): -163.29.

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[0221] Intermediate 7h is prepared as follows:

to. 5-Fluoro-7- (2,3,5-tN-O-benzoM-p-D-NbofuransN) -4- (1-tritiMH-imidazol-4-M) -7H-pyrrolo [2,3-

d] pyrimidine (7h). Ethylmagnesium bromide (1 M sol in THF, 1.84 ml, 1.84 mM) is added to a solution purged with 4-iodine-1-trityl-IH-imidazole argon (696 mg, 1.6 mM ) in dry THF (6 ml) and the resulting solution is stirred for 10 minutes at room temperature, followed by the addition of a solution of ZnCh (1 M sol in THF, 3.2 ml, 3.2 mM) . The mixture is stirred for 2 hours at room temperature and the resulting white spice solution is transferred to an argon purged flask with 6-chloro-7-fluorodeazapurine ribosides (493 mg, 0.8 mM) and Pd (PPh3) 4 (46 mg, 0.04 mM) and stirred at 95 ° C for 12 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous EDTA (sat., 20 mL). The aqueous layer is reextracted with chloroform (2 X 5 milliliters). The collected organic extracts are dried over MgSO4, evaporated and exposed to silica chromatography (hexanes-AcOEt, 2: 1) generating the product 7h (386 mg, 5 of 4%) in the form of an orange foam. 1HNMR (600MHz, CDCl3): 4.67 (dd, 1H, Jgem = 12.2, JSb # = 3.9, H-5’b); 4.77 (ddd, 1H, J ^ s = 3.9, 3.2, J43 = 3.7, H-4 '); 4.84 (dd, 1H, Jgem = 12.2, J3'a4' = 3.2, H-5'a); 6.04 (dd, 1H, Ja z = 5.8, J3 4 '= 3.7, H-3'); 6.07 (t, 1H, Jzr = Jz3 = 5.8, H-2 ’); 6.84 (dd, 1H, JV2 = 5.8, Jhf = 1.0, H-1’); 7.13 (bs, 1H, H-6); 7.16-7.20 (m, 6H, H- or -Tr); 7.32-7.38 (m, 11H, H-m, p-Try H-m-Bz); 7.41 and 7.48 (2 X m, 2 X 2H, H-m-Bz); 7.53, 7.58 and 7.59 (3 X m, 3X1H, H-p-Bz); 7.69 (bs, 1H, H-2-imidazole); 7.84 (d, 1H, J3.2 = 1.3, H-5-imidazole); 7.90, 8.01 and 8.12 (3 X m, 3X2H, H-o-Bz); 8.83 (s, 1H, H-2). 13C NMR (151 MHz, CDCl3): 63.81 (CH2-5 ’); 71.46 (CH-3 ’); 73.71 (CH-2 ’); 76.42 (C-Tr); 80.36 (CH-4’); 85.25 (CH-1 ’); 104.39 (d, Jc, f = 16, C-4a); 108.13 (b, CH-6); 125.70 (d, Jc, f = 16, CH-5-imidazole); 128.28,128.46,128.53 (CH-m-Bz and CH-m, p-Tr); 128.67 (C - / - Bz); 128.70 (CH-m-Bz); 129.27 (C - / - Bz); 129.65, 129.72 and 129.81 (CHo-Bz and CH-o-Tr); 133.49 and 133.72 (CH-p-Bz); 137.17 (C-4- imidazole); 140.21 (CH-2-imidazole); 141.64 (C / -Tr); 143.02 (d, Jc, f = 251, C-5); 148.11 (C-4 and C-7a); 152.22 (CH-2); 165.09, 165.40 and 166.11 (CO). 19F NMR (470.3 MHz, CDCl3): -158.87.

Example 27. 5-Fluoro-7- (P-D-ribofuransN) -4- (pyrrol-3-N) -7H-pyrrolo [2,3-d] pyrimidma (8i).

[0222]

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[0223] To a mixture purged with argon of unprotected ribosides 9 (177 mg, 0.58 mM), 1- (triisopropylsilyl) -1H-pyrrole-3-boronic acid (195 mg, 0.73 mM), Cs2 ( CO3) 2 (570 mg, 1.75 mM) a prepared solution of Pd (OAc) 2 (6.5 mg, 0.029 mM) and TPPTS (41 mg, 0.07 mM) in water / CH3CN (2: 1) is added , 3 mL). The reaction mixture is stirred at 100 ° C for 3 hours. After cooling, the mixture is neutralized by the addition of aqueous HCl (3M sol.), Co-evaporated with silica and a chromatography on the silica column (5% ^ 7% MeOH in CHCl3) is exposed generating product 8i (141 mg, 73%) in the form of a white solid. The compound crystallizes from MeOH facilitating a white powder. 1H NMR (600 MHz, DMSO-d6): 3.55 (ddd, 1H, Jgem = 12.0, J5’bOH = 5.6, JSb, 4 ’= 4.0, H-5’b); 3.63 (ddd, 1H, Jgem = 12.0, J ^ oh = 5.4, J3’a4 ’= 4.1, H-5’a); 3.90 (ddd, 1H, J4’5 ’= 4.1, 4.0, J4’3’ = 3.4, H-4 ’); 4.09 (td, 1H, JS2 = Jsoh = 4.9, J34 ’= 3.4, H-3’); 4.35 (ddd, 1H, J2, oh =

6.4, J21 ’= 6.1, J23’ = 4.9, H-2 ’); 5.09 (dd, 1H, Joh5’ = 5.6, 5.4, OH-5 ’); 5.19 (d, 1H, Joh3 ’= 4.9, OH-3’); 5.40 (d, 1H, JoHz = 6.4, OH-2 ’); 6.27 (dd, 1H, Jrz = 6.1, Jhf = 1.9, H-1’); 6.88 (ddd, 1H, J45 = 2.9, J4nh = 2.4, J4.2 = 2.0, H-4- pyrr); 6.92 (ddd, 1H, J54 = 2.9, J5NH = 2.7, J52 = 1.5, H-5-pyrr); 7.69 (ddd, 1H, J2NH = 2.9, J24 = 2.0, J25 = 1.5, H-2- pyrr); 7.80 (d, 1H, JHF = 1.7, H-6 ); 8.66 (s, 1H, H-2); 11.42 (bs, 1H, NH). 13C NMR (151 MHz, DMSO-cfe): 61.70 (CH2-5 '); 70.69 (CH-3'); 74.18 (CH-2 '); 85.30 (CH-4') ; 86.27 (CH-1 ’); 102.66 (d, Jcf = 16, C-4a); 108.58 (d, Jcf = 8, CH-4-pyrr); 108.80 (d, JcF = 31, CH-6); 119.85 (CH-5-pyrr); 121.51 (C-3-pyrr); 122.07 (d, Jcf = 13, CH-2-pyrr); 142.09 (d, JcF = 246, C-5); 147.45 (d, JcF = 3, C-7a); 151.94 (CH-2); 153.47 (d, Jcf = 4, C-4). 19F NMR (470.3 MHz, DMSO-d6, ref (C6F6) = - 163ppm): - 161.58.IR (KBr): v = 1572, 1547, 1465, 1427, 1062, 1024 cm'1. MS FAB, m / z (rel.%): 203 (100), 335 (35) [M + H] .HRMS (FAB): calcd for C13H16FN4O4 [M + H] 335.1156, found 335.1156.

[0224] Intermediate 9 is prepared as follows:

to. 4-Chloro-5-fluoro-7- [2,3-O-isopropylidene-5-O-tert-butyldimethylsilyl-p-D-ribofuranosyl] -7H-

pyrrolo [2,3-d] pyrimidine (12). Tris (dimethylamino) -phosphine (706 microliters, 3.9 mM) is added dropwise to a stirred solution of 2,3-O-isopropylidene-5-O-tert-butyldimethylsilyl-pD-ribofuranose (914 mg, 3 mM) and carbon tetrachloride (468 microliters, 4.5 mM) in toluene (5 mL) for 35 minutes at -30

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° C. The temperature of the reaction mixture rose to 0 ° C for one hour. The mixture was washed with ice-cold brine (5 ml), dried over MgSO4 and added to a stirred mixture of 4-chloro-5-fluoropyrrolo [2,3-d] pyrimidine 10 (343 mg, 2 mM), kOh in powder (253 mg, 4.5 mM) and TDA-1 (320 mL, 1 mM) in toluene (5 mL). The mixture was stirred for 24 hours and then saturated NH4Cl (20 mL) was added and the mixture was extracted with chloroform (20 ml, and then 2 X 5 milliliters). The collected organic extracts were dried over MgSO4, evaporated and exposed to silica chromatography (hexanes-AcOEt, 22: 1) generating product 12 (390 mg, 40 and 3%) as a colorless oil. 1H NMR (600 MHz, CDCla): 0.10 and 0.11 (2 X s, 2 X 3H, CHaSi); 0.92 (s, 9H, (CH3) 3C); 1.38 (q, 3H, J = 0.5, (CH3) 2C); 1.65 (q, 3H, J = 0.5, (CH3) 2C); 3.81 (dd, 1H, Jgem = 11.4, JSb4 ’= 3.2, H-5’b); 3.91 (dd, 1H, Jgem = 11.4, J5'a, 4 '= 2.9, H-5'a); 4.38 (ddd, 1H, J4', 5 '= 3.2, 2.9, J ^ '= 2.4, H-4'); 4.91 (dd, 1H, Js, 2 = 6.2, Ja4 '= 2.4, H-3'); 4.93 (dd, 1H, Jza = 6.2, Jzr = 2.6, H -2'); 6.47 (dd, 1H, Jrz = 2.6, Jhf = 1.5, H-1 ’); 7.44 (d, 1H, Jhf = 2.5, H-6); 8.65 (s, 1H, H-2) .13cNMR (151 MHz, CDCl3): -5.33 and -5.44 ( CH3Si); 18.38 (C (CH3) 3); 25.41 ((CH3) 2C); 25.87 ((CH3) 3C); 27.33 ((CH3) 2C); 63.53 (CH2-5 ’); 80.73 (CH-3 ’); 85.32 (CH-2 ’); 86.19 (CH-4 ’); 90.16 (CH-1 ’); 107.56 (d, JcF = 14, C-4a); 107.62 (d, Jc, F = 27, CH-6); 114.24 (C (CH3 ^); 141.49 (d, Jcf = 253, C-5); 146.50 (d, JcF = 1, C-7a); 150.54 (d, JcF = 4, C-4); 151.66 (CH-2) .19F NMR (470.3 MHz, CDCl3, ref (C6F6) = -163 ppm): -168.82.

b. 4-Chloro-5-fluoro-7-p-D-ribofuranosyl-7H-pyrrolo [2,3-d] pyrimidine (9). Protected nucleosides 12 (350 mg, 0.76 mM) are treated with 90% aqueous TFA (1 ml) for 2 hours. The volatiles are evaporated in the vacuum and the residues are co-evaporated several times with MeOH. Chromatography on silica (4% MeOH in chcI3) generates free nucleosides 9 (198 mg, 85%) as a white foam. 1H NMR (600 MHz, DMSO-cfe): 3.56 (ddd, 1H, Jgem = 12.0, JabOH = 5.4 ’, J3’b4’ =

3.9, H-5’b); 3.64 (ddd, 1H, Jgem = 12.0, JaaOH = 5.4, Jaa4 ’= 4.0, H-5’a); 3.93 (ddd, 1H, J4 5 ’= 4.0, 3.9, J ^ a = 3.3, H-4’); 4.10 (td, 1H, J3z = J3oh = 5.0, J3.4 ’= 3.3, H-3’); 4.33 (ddd, 1H, J2oh = 6.2, J2r = 5.9, Jza = 5.0, H-2 '); 5.09 (t, 1H, Joh5' = 5.4, OH-5 '); 5.22 (d, 1H, Joh3 ’= 5.0, OH-3’); 5.44 (d, 1H, Johz = 6.2, OH-2 ’); 6.25 (dd, 1H, Jrz = 5.9, Jhf = 1.9, H-1 ’); 8.02 (d, 1H, Jhf = 2.0, H-6); 8.70 (s, 1H, H-2). 13c NMR (151 MHz, DMSO-cfe): 61.48 (cH2-5 ’); 70.55 (cH-3 ’); 74.53 (cH-2 ’); 85.66 (cH-4 ’); 86.98 (cH-1 ’); 106.55 (d, Jc, f = 14, c-4a); 111.42 (d, JcF = 27, cH-6); 140.45 (d, Jcf = 249, c-5); 146.97 (d, Jcf = 1, c-7a); 149.09 (d, Jcf = 4, c-4); 151.65 (cH-2) .19FNMR (470.3 MHz, DMSOd ref ^ 6) = -163 ppm): -169.72.

Example 28. 5-Chloro-4-fenM-7- (P-D-nbofuransN) -7H-pyrrolo [2,3-d] pmmidma (15a).

[0225]

image43

[0226] Compound 14a (409 mg, zero, 61 mM) is treated with 1 M NaOMe / MeOH (185 microliters, 0.185 mM) in MeOH (5 mL) for 12 hours at room temperature. The mixture is co-evaporated with silica and a chromatography on the silica column (3% MeOH in chcI3) is exposed, generating the product 15a (200 mg, 91%) as a colorless solid. Crystallization from MeOH / AcOEt / hexane gave a white powder. 1H NMR (600 MHz, DMSO-d6): 3.58 (ddd, 1H, Jgem = 11.9, Jab oh = 5.4, Jab4 ’= 3.9, H-5’b); 3.66 (ddd, 1H, Jgem = 11.9, Ja’aOH = 5.2, JSa4 ’= 4.1, H-5’a); 3.95 (ddd, 1H, J4 5 ’= 4.1, 3.9, J ^ a = 3.3, H-4’); 4.13 (td, 1H, J32 ’= J3oh = 4.9, J3.4’ = 3.3, H-3 ’); 4.43 (ddd, 1H, J2oh = 6.3, J2r = 6.1, J23 ’= 4.9, H-2’); 5.13 (dd, 1H, Joh5 ’= 5.4,

5.2, OH-5 ’); 5.24 (d, 1H, Joh.s ’= 4.9, OH-3’); 5.47 (d, 1H, Johz = 6.3, OH-2 ’); 6.36 (d, 1H, Jr, 2 = 6.1, H-1 ’); 7,537.58 (m, 3H, H-m, p-Ph); 7.76 (m, 2H, H-o-Ph); 8.17 (s, 1H, H-6); 8.94 (s, 1 H, H-2). 13c NMR (151 MHz, DMSO-d6): 61.57 ((cH2-5 '); 70.68 (cH-3'); 74.42 (cH-2 '); 85.64 (cH-4' ); 86.74 (cH-1 '); 103.36 (c-5); 113.01 (c-4a); 125.46 (cH-6); 128.07 (cH-m-Ph); 130.04 (cH-p-Ph); 130.36 (cH-o-Ph); 136.54 (c - / - Ph); 150.71 (c-7a); 151.74 (cH-2) ; 158.81 (c-4) .IR (KBr): v = 1560,1460,1441, 1343, 1199, 1124, 1103, 1084, 1075, 1044, 984 cm'1. MS FAB, m / z (rel .%): 230 (100), 362 (15) [M + H] .HRMS (FAB): calcd for ^ 7 ^ 7 ^ 304 [M + H] 362.0908, found 362.0922.

[0227] Intermediate compound 14a is prepared as follows:

to. 5-Chloro-4-phenyl-7- (2,3,5-tri-O-benzoyl-p-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimide (14a).

An argon purged mixture of 6,7-dichloro-7-deazapurine 13 protected ribosides (394 mg, 0.62

mM), phenylboronic acid (91 mg, 0.75 mM), K2c03 (172 mg, 1.25 mM) and Pd (Pph3) 4 (36 mg, 0.031 mM)

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in toluene (3 mL) it is stirred at 100 ° C for 4 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous NH4Cl (sat., 20 mL), the aqueous phase is reextracted with chloroform (2 X 5 milliliters). The collected organic extracts are dried over MgSO4, the volatiles are removed to the ford and residues are exposed to silica chromatography (hexanes-AcOEt, 7: 1) generating the product 14a (398 mg, 95%) in the form of a yellowish foam. 1H NMR (600 MHz, CDCl3): 4.71 (dd, 1H, Jgem = 12.2, Jsb4 '= 3.7, H-5'b); 4.82 (ddd, 1H, J4'3 = 4 , 6, J ^ s = 3.7, 3.1, H-4 '); 4.90 (dd, 1H, Jgem = 12.2, JSa4 '= 3.1, H-5'a); 6.14 (dd, 1H, J32 '= 5.9, J34' = 4.6, H-3 '); 6.21 (dd, 1H, J23 = 5.9, J2V = 5.5, H-2 '); 6.81 (d, 1H, Jrz =

5.5, H-1 '); 7.37 (m, 2H, H-m-Bz); 7.40 (s, 1H, H-6); 7.41 (m, 2H, H-m-Bz); 7.47-7.52 (m, 5H, H-m, p-Ph and H-m-Bz); 7.55, 7.59 and 7.60 (3xm, 3X1H, H-p-Bz); 7.77 (m, 2H, H-o-Ph); 7.96, 8.01 and 8.14 (3 X m, X 3 2H, H-o-Bz); 8.94 (s, 1H, H-2) .13CNMR (151MHz, CDCl3): 63.57 (CH2-5 '); 71.37 (CH-3 '); 73.94 (CH-2 '); 80.35 (CH-4 '); 86.15 (CH-1 '); 106.44 (C-5); 114.15 (C-4a); 123.36 (CH-6); 127.87 (CH-m-Ph); 128.41 (C - / - Bz); 128.50 and 128.53 (CH-m-Bz); 128.66 (C - / - Bz); 128.71 (CH-m-Bz); 129.30 (C - / - Bz); 129.69, 129.81 and 129.84 (CH-o-Bz); 129.88 (CH-p-Ph); 130.25 (CH-o-Ph); 133.51,133.73 and 133.76 (CH-p-Bz); 136.22 (C - / - Ph); 150.88 (C-7a); 152.05 (CH-2); 160.10 (C-4); 165.11,165.38 and166.14 (CO) .MS FAB, m / z (rel.%): 674 (100) [M + H ]. HR MS (FAB): calcd for C ^ gClNsOy [M + H] 674.1694, found 674.1695.

Example 29. 5-Chloro-4- (furan-2-N) -7- (P-D-NbofuranesM) -7H-pyrrolo [2,3-d] pinmidma (15b).

[0228]

image44

[0229] Compound 14b (197 mg, 0.30 mM) is treated with 1 M NaOMe / MeOH (60 microliters, 0.06 mM) in MeOH (5 mL) for 12 hours at room temperature. The mixture is desalinated with Dowex 50 in a pyridinium form and the crystallization of the residue from MeOH / CHCl3 facilitates a yellow powder and the reverse phase chromatography of the mother liquors facilitates an additional portion of the desired product. The total generation of product 15b is 91 mg (86%). 1H NMR (400 MHz, DMSO-cfe): 3.58 and 3.66 (2 3 ddd, 2H, Jgem = 12.0, Ja'OH = 5.4, J54 '= 3.9, H-5' ); 3.94 (q, 1H, JX3 = 3.9, J43 = 3.4, H-4 '); 4.12 (td, 1H, J3Z = 5.0, J3oh =

4.9, Js'4 '= 3.4, H-3'); 4.40 (td, 1H, J2oh = 6.2, J2V = 6.0, JZ3 = 5.0, H-2 '); 5.12 (t, 1H, Joh5 '= 5.4, OH-5'); 5.21 (d, 1H, Joh3 '= 4.9, OH-3'); 5.45 (d, 1H, Joh2- 6.2, OH-2 '); 6.29 (d, 1H, JV2 = 6.0, H-1 '); 6.79 (dd, 1H, J43 = 3.5, J4 5 = 1.7, H-4-furyl); 7.43 (dd, 1H, J34 = 3.5, J33 = 0.8, H-3-furyl); 8.06 (dd, 1H, J54 = 1.7, J53 = 0.8, H-5-furyl); 8.17 (s, 1H, H-6); 8.84 (s, 1H, H-2). 13C NMR (100.6 MHz, DMSO-cfe): 61.48 (CH2-5 '); 70.57 (CH-3 '); 74.38 (CH-2 '); 85.55 (CH-4 '); 86.67 (CH-1'); 103.40 (C-5); 110.67 (C-4a); 112.76 (CH-4-furyl); 115.42 (CH-3-furyl); 125.95 (CH-6); 146.47 (CH-5-furyl); 147.15 (C-4); 150.86 (C-2-furyl); 151.26 (C-7a); 151.41 (CH-2). IR (KBr): v = 1627, 1586, 1556,1454, 1335,1105, 1060,984cm'1. MS FAB, m / z (rel.%): 220 (60), 352 (100) [M + H]. HR MS (FAB): calcd for C15H15ClN3O5 [M + H] 352.0700, found 352.0698.

[0230] Intermediate compound 14b is prepared as follows:

to. 5-Chloro-4- (furan-2-yl) -7- (2,3,5-tri-O-benzoyl-p-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (14b).

A mixture purged with riboside argon of 6,7-dichloro-7-deazapurine 13 (207 mg, 0.327 mM), 2- (tributylstanyl) furan (125 microliters, 0.40 mM) and PdCl2 (PPh3) 2 (12 mg , 0.02 mM) in DMF (2 mL) is stirred at 100 ° C for 2 hours. The volatiles are removed to the ford and the residue is co-evaporated several times with toluene. A column chromatography on silica (hexanes-AcOEt, 10: 1 ^ 6: 1) generates the product 14b (215 mg, 99%) as a yellow foam. 1H nMr (400 MHz, CDCl3):

4.70 (dd, 1H, Jgem = 12.2, J & b4 '= 3.7, H-5'b); 4.80 (dt, 1H, J * s = 4.4, JAS = 3.7, 3.1, H-4 '); 4.89 (dd, 1H, Jgem = 12.2, J5'a4 '= 3.1, H-5'a); 6.11 (dd, 1H, J3Z = 5.8, J34 '= 4.4, H-3'); 6.16 (t, 1H, JZ3 = 5.8, J2X = 5.5, H-2 '); 6.62 (dd, 1H, J43 = 3.5, J45 = 1.8, H-4- furilo); 6.79 (d, 1H, Jr2 = 5.6, H-1 '); 7.36 and 7.41 (2 X m, 2 X 2H, H-m-Bz); 7.42 (s, 1H, H-6); 7.47 (dd, 1H, J34 = 3.5, J33 = 0.8, H-3-furyl); 7.50 (m, 2H, H-m-Bz); 7.54, 7.58 and 7.61 (3Xm, 3X1H, H-p-Bz). 7.71 (dd, 1H, J54 = 1.8, J53 = 0.8, H-5-furyl); 7.94, 8.00 and 8.14 (3 X m, 3 X2H, H-o-Bz); 8.85 (s, 1H, H-2). 13C NMR (100.6 MHz, CDCl3): 63.60 (CH2-5 '); 71.42 (CH-3 '); 73.99 (CH-2 '); 80.40 (CH-4'); 86.01 (CH-1 '); 106.28 (C-5); 111.89 (C-4a); 112.22 (CH-4-furyl); 116.15 (CH-3-furyl); 123.75 (CH-6); 128.45 (C - / - Bz); 128.48,128.53 and 128.73 (CH-m-Bz); 129.34 (C - / - Bz); 129.70, 129.82 and 129.85 (CH-o-Bz); 133.49 and 133.71 (CHp-Bz); 145.42 (CH-5-furyl); 148.41 (C-4); 150.54 (C-2-furyl); 151.49 (C-7a); 151.82 (CH-2); 165.08, 165.37 and 166.14 (CO). MS FAB, m / z (rel.%): 175 (100), 664 (65) [M + H]. HR MS (FAB): calcd for C ^ and ClNsOs [M + H] 664.1487, found 664.1495.

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Example 30. 5-Chloro-7- (P-D-ribofuransN) -4- (thiophen-2-M) -7H-pyrrolo [2,3-d] pinmidma (15c).

[0231]

image45

[0232] Compound 14c (183 mg, 0.27 mM) is treated with 1M NaOMe / MeOH (60 pL, 0.06 mM) in MeOH (5 mL) for 12 hours at room temperature. The mixture is desalinated with Dowex 50 in a pyridinium form and crystallization of the residue from MeOH / CHCl3 facilitates white powder and reverse phase chromatography of the mother liquors facilitates an additional portion of the desired product. The total production of product 15c is 93 mg (94%). 1H NMR (400 MHz, DMSO-de): 3.58 and 3.67 (2 3 ddd, 2H, Jgem = 12.0, J & oh = 5.5, Js4 '= 3.8, H-5'); 3.95 (q, 1H, J4.5 = 3.8, J * 3 '= 3.4, H-4'); 4.13 (td, 1H, JS2 = 5.0, J30H = 4.9, Js # = 3.4, H-3 '); 4.41 (td, 1H, J2oh = 6.2, J2r = 6.0, J2S = 5.0, H-2 '); 5.12 (t, 1H, Joh5 '= 5.5, OH-5'); 5.22 (d, 1H, Joh3 '= 4.9.0H-3'); 5.46 (d, 1H, Joh2 '= 6.2, OH-2'); 6.30 (d, 1H, Jr2 = 6.0, H-1 '); 7.29 (dd, 1H, J45 = 5.0, J43 = 3.8, H-4- thienyl); 7.89 (dd, 1H, J5A = 5.0, J3.3 = 1.1, H -5-thienyl); 8.06 (dd, 1H, J3.4 = 3.8, J3.5 = 1.1, H-3-thienyl); 8.19 (s, 1H, H-6); 8.83 (s, 1H, H-2). 13C NMR (100.6 MHz, DMSO-de): 61.48 (CH2-5 '); 70.56 (CH-3 '); 74.41 (CH-2 '); 85.57 (CH-4 '); 86.79 (CH-1'); 102.94 (C-5); 111.24 (C-4a); 125.85 (CH-6); 128.46 (CH-4-thienyl); 131.30 (CH-5-thienyl); 132.36 (CH-3-thienyl); 140.54 (C-2-thienyl); 151.15 (C-7a); 151.31 (CH-2); 151.70 (C-4). %): 236 (75), 368 (100) [M + H] .IR (KBr): v = 1556,1454, 1351, 1282, 1098, 1035, 975 cm'1. HR MS (FAB): calcd for C ^ H ^ dN ^ S [M + H] 368.0472, found 368.0480. Anal. Calcd for C ^ H ^ CIN ^ S: C, 48.98; H, 3.84; N, 11.42. Found: C, 48.68; H, 3.76; N, 11.13.

[0233] Intermediate compound 14c is prepared as follows:

а. 5-Chloro-4- (thiophen-2-yl) -7- (2,3,5-tri-O-benzoyl-p-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (14c).

An argon purged mixture of 6,7-dichloro-7-deazapurine 13 (207 mg, 0.327 mM), 2- (tributylstanyl) thiophene (127 pL, 0.40 mM) and PdCh (PPh3) 2 (12 mg, 0.02 mM) in DMF (3 mL) is stirred at 100 ° C for 2 hours. The volatiles are removed from the ford and the residue is co-evaporated several times with toluene. A silica column chromatography (hexanes-AcOEt, 20: 1 ^ 6: 1) generates the product 14c (198 mg, 89%) as a foam. 1H NMR (400 MHz, cDcI3): 4.70 (dd, 1H, Jgem = 12.2, J5'b, 4 '= 3.7, H-5'b); 4.81 (dt, 1H, J *, 3 '= 4.4, J *, 5' = 3.7, 3.1, H-4 '); 4.89 (dd, 1H, Jgem = 12.2, J5a4 = 3.1, H-5'a); 6.11 (dd, 1H, JS2 = 5.8, Js * = 4.4, H-3 '); 6.16 (t, 1H, J2S = 5.8, J2r = 5.6, H-2 ');

б, 80 (d, 1H, Jr, 2 = 5.6, H-1 '); 7.18 (dd, 1H, J45 = 5.1, J43 = 3.8, H-4-thienyl); 7.36 and 7.41 (2 X m, 2 X 2H, H-

m-Bz); 7.42 (s, 1H, H-6); 7.50 (m, 2H, H-m-Bz); 7.54 (m, 1H, H-p-Bz); 7.57 (dd, 1H, J54 = 5.1, J33 = 1.1, H-5-thienyl); 7.58 and 7.61 (2 X m, 2 X 1H, H-p-Bz); 7.94 and 8.11 (2 X m, 2 X 2H, H-o-Bz); 8.03 (dd, 1H, J34 =

3.8, J3.5 = 1.1, H-3-thienyl); 8.14 (m, 2H, H-o-Bz); 8.83 (s, 1H, H-2). 13C NMR (100.6 MHz, CDCl3): 63.63 (CH2-5 '); 71.45 (CH-3'); 73.99 (CH-2 '); 80.46 (CH-4 '); 86.02 (CH-1 '); 106.00 (C-5); 112.57 (C-4a); 123.52 (CH-6); 127.88 (CH-4-thienyl); 128.45 (C - / - Bz); 128.49 and 128.54 (CH-m-Bz); 128.71 (C - / - Bz); 128.74 (CH-m-Bz); 129.34 (C - / - Bz); 129,70,129.83 and 129.86 (CH-o-Bz); 130.27 (CH-5-thienyl); 132.47 (CH-3-thienyl); 133.51,133.72 and133.73 (CH-p-Bz); 140.50 (C-2-thienyl); 151.41 (C-7a); 151.72 (CH-2); 153.19 (C-4); 165.09,165.38 and166.14 (C0) .MSFAB, m / z (rel.%): 680 (100) [M + H]. HR MS (FAB): calcd for

C36H27ClN30yS [M + H] 680,1258, found 680,1264.

Example 31. 5-Chloro-4- (furan-3-yl) -7- (P-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine (15d).

[0234]

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image46

[0235] Compound 14d (166 mg, 0.55 mM) is treated with 1M NaOMe / MeOH (165 pL, 0.165 mM) in MeOH (5 ml_) for 12 hours at room temperature. The mixture is co-evaporated with silica and exposed to a chromatograph on the silica column (4% MeOH in CHCL) generating the product 15d (155 mg, 80%) as a white solid. A crystallization from MeOH / CHCl3 generates white crystals. 1H NMR (600 MHz, DMSO-de): 3.57 (ddd, 1H, Jgem = 12.0, J5bOH = 5.4, J5’b4 ’= 3.9, H-5’b); 3.66 (ddd, 1H, Jgem = 12.0, J5aoH =

5.3, J5 ’4 = 4.0, H-5’a); 3.94 (ddd, 1H, J4’5 = 4.0, 3.9 J4 “3” = 3.2, H-4 ”); 4.12 (ddd, 1H, J3 0h = 4.8, J3’2 = 4.7, J3’4 ’= 3.2, H-3’); 4.40 (ddd, 1H, J? V = 6.1, J2 0h = 5.8, J2 3 ’= 4.7, H-2’); 5.14 (dd, 1H, J0H5 ’= 5.4, 5.3, OH-5’); 5.24 (d, 1H, J0H3 ’= 4.8, OH-3’); 5.47 (d, 1H, J0hz = 5.8, OH-5 ’); 6.29 (d, 1H, JV2 = 6.1, H-1 ’); 7.08 (dd, 1H, J4) 5 = 1.9, J42 = 0.8, H-4-furyl); 7.86 (dd, 1H, J54 = 1.9, J52 = 1.6, H-5-furyl); 8.14 (s, 1H, H-6); 8.37 (dd, 1H, J25 = 1.6, J24 = 0.8, H-2-furyl); 8.86 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-d6): 61.59 (CH2-5 ’); 70.68 (CH-3 ’); 74.46 (CH-2 ’); 85.63 (CH-4 ’); 86.72 (CH-1 ’); 103.11 (C-5); 111.71 (CH-4-furyl); 112.67 (C-4a); 123.30 (C-3-furyl); 125.38 (CH-6); 143.95 (CH-5-furyl); 145.67 (CH-2-furyl); 150.74 (C-7a); 151.39 (C-4); 151.75 (CH-2). IR (KBr): v = 1562, 1461, 1426, 1105, 1040, 984 cm'1. MSFAB, m / z (rel.%): 352 (100) [M + H]. HR MS (FAB): calcd for C15HI5CIN3O5 [M + H] 352.0700, found 352.0715.

[0236] Intermediate compound 14d is prepared as follows:

to. 5-Chloro-4- (furan-3-yl) -7- (2,3,5-tri-0-benzoyl-p-D-ribofuranosyl) -7H-pyrrolo [2,3-

d] pyrimidine (14d). A mixture purged with argon of 6,7-dichloro-7- deazapurine 13 protected ribosides (506 mg, 0.8 mM), furan-3-boronic acid (117 mg, 1.04 mM), K2C03 (221 mg, 1.60 mM) and Pd (PPh3) 4 (46 mg, 0.04 mM) in toluene (5 mL) is stirred at 100 ° C for 10 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous NH4CI (sat., 20 mL), the aqueous phase is extracted again with chloroform (2X5 milliliters). The organic extracts collected are dried over MgSO4, the volatiles are removed in vacuo and the residue is exposed to silica chromatography (hexanes-AcOEt, 7: 1) generating the product 14d (457 mg, 86%) in the form of a yellowish foam . 1H NMR (600 MHz, CDCI3): 4.70 (dd, 1H, Jgem = 12.2, J5b4 ’= 3.7, H-5’b); 4.81

(ddd, 1H, J4 ’, 3’ = 4.4, J4 ’, 5’ = 3.7, 3.1, H-4 ’); 4.89 (dd, 1 H, Jgem = 12.2, J5a, 4 ’= 3.1, H-5’a); 6.12 (dd, 1 H, J3 \ 2 ’= 5.8, j3 \ 4’ = 4.4, H-3 ’); 6.17 (dd, 1H, J2.3 = 5.8, J2, v = 5.6, H-2 ’); 6.79 (d, 1H, JVt2> = 5.6, H-1 ’); 7.06 (dd, 1 H, J4j5 = 1, 9, J4j2 = 0.8, H-4-furyl); 7.37 (m, 2H, H-m-Bz); 7.39 (s, 1 H, H-6); 7.41 and 7.50 (2 X m, 2X2H, H-m-Bz); 7.53 (dd, 1H, J5.4 = 1.9, J5.2 = 1.5, H-5-furyl); 7.54, 7.58 and 7.61 (3 X m, 3 X 1H, H-p-Bz); 7.94,8.00 and 8.14 (3Xm, 3X2H, H-o-Bz); 8.18 (dd, 1H, J2.5 = 1.5, J2.4 = 0.8, H-2-furyl); 8.86 (s, 1H, H-2) .13 CNMR (151 MHz, CDCI3): 63.60 (CH2-5 ’); 71.40 (CH-3 ’); 73.93 (CH-2 ’); 80.38 (CH-4 ’); 85.97 (CH-1 ’); 105.89 (C-5); 111.32 (CH-4-furyl); 113.70 (C-4a); 123.13 (C-3-furyl); 123.25 (CH-6); 128.39 (C - / - Bz); 128.49 and 128.54 (CH-m-Bz); 128.65 (C - / - Bz); 128.73 (CH-m-Bz); 129.29 (C - / - Bz); 129.69,

129.82y129.84 (CH-o-Bz); 133.53,133.74y133.75 (CH-p-Bz); 143.01 (CH-5-furyl); 145.42 (CH-2-furyl);

150.92 (C-7a); 152.02 (CH-2); 152.54 (C-4); 165,10,165.39 and166.14 (CO) .MS FAB, m / z (rel.%): 445 (50), 664 (100) [M + H]. HR MS (FAB): calcd for C36H27CIN308 [M + H] 664.1487, found

664.1467.

Example 32. 5-Chloro-7- (p-D-ribofuranosyl) -4- (thiophen-3-yl) -7H-pyrrolo [2,3-d] pyrimidine (15e).

[0237]

image47

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[0238] Compound 14e (480 mg, 0.71 mM) is treated with 1M NaOMe / MeOH (212 pl, 0.212 mM) in MeOH (5 mL) for 12 hours at room temperature. The mixture is co-evaporated with silica and a chromatograph is exposed on the silica column (4% MeOH in CHCI3) generating the product 15e (225 mg, 87%) as a colorless solid. A crystallization from MeOH facilitates hard beige prisms. 1H NMR (600 MHz, DMSO-cfe): 3.57 (ddd, 1H, Jgem = 12.0, J & bOH = 5.4, J & b4 '= 4.0, H-5'b); 3.66 (ddd, 1H, Jgem = 12.0, JsaOH = 5.3, J5'a4 '= 4.1, H-5'a); 3.94 (ddd, 1H, J4 5 '4.1, 4.0 J4 3' = 2.9, H-4 '); 4.12 (ddd, 1H, JSoh = 4.6, JS2 = 4.3, Jj4 '= 2.9, H-3'); 4.41 (ddd, 1H, J2v = 6.1, J2oh = 5.4, J22 = 4.3, H-2 '); 5.14 (dd, 1H, Joh5 '= 5.4, 5.3, OH-5'); 5.24 (d, 1H, Joh3 '= 4.6, OH-3'); 5.47 (d, 1H, Joh2 '= 5.4, OH-5'); 6.30 (d, 1H, JX2 = 6.1, H-1 '); 7.61 (dd, 1H, J45 = 5.0, J42 = 1.3, H-4-thienyl); 7.69 (dd, 1H, J5A = 5.0, J5a = 2.9, H-5-thienyl); 8.12 (dd, 1H, JZ5 = 2.9, J2.4 = 1.3, H-2-thienyl); 8.15 (s, 1 H, H-6); 8.88 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-cfe): 61.60 ((CH2-5 '); 70.70 (CH-3'); 74.46 (CH-2 '); 85.65 (CH-4' ); 86.73 (CH-1 '); 103.33 (C-5); 112.74 (C-4a); 125.46 (CH-6); 126.26 (CH-5- thienyl); 129.35 (CH-4-thienyl); 129.94 (CH-2-thienyl); 138.02 (C-3-thienyl); 150.87 (C-7a); 151.69 (CH-2) ; 153.90 (C-4) .IR (KBr): v = 1632,1579,1568,1463,1447, 1437, 1195, 1131, 1124, 1090, 1069, 1037, 1026, 996, 987 cm'1. MS FAB, m / z (rel.%): 236 (80), 368 (100) [M + H] .HR MS (FAB): calcd for C15H15CIN3O4S [M + H] 368.0472, found 368.0471. Anal. Calcd for C15H14CIN3O4S-1.35CHsOH: C, 47.77; H, 4.76; N, 10.22. Found: C, 47.74; H, 4.70; N, 10.28.

[0239] Intermediate compound 14e is prepared as follows:

to. 5-Chloro-4- (thiophen-3-yl) -7- (2,3,5-tri-O-benzoyl-p-D-ribofuranosyl) -7H-pyrrolo [2,3-d] pyrimidine

(14e). A mixture purged with argon of 6,7-dichloro-7-deazapurine 13 protected ribosides (506 mg, 0.8 mM), thiophene-3-boronic acid (133 mg, 1.04 mM), K2CO3 (221 mg, 1.60 mM) and Pd (PPh3) 4 (46 mg, 0.04 mM) in toluene (5 mL) is stirred at 100 ° C for 10 hours. The mixture is diluted with chloroform (20 ml) and washed with aqueous NH4CI (sat., 20 mL), the aqueous phase is extracted again with chloroform (2 X 5 milliliters). The collected organic extracts are dried over MgSO4, the volatiles are removed in vat and the residue is exposed to silica chromatography (hexanes-AcOEt, 6: 1) generating the product 14e (500 mg, 92%) in the form of a yellowish foam . * H NMR (600 MHz, CDCI3): 4.70 (dd, 1H, Jgem = 12.2, J5'b4 '= 3.7, H-5'b); 4.81 (ddd, 1H, JX2 = 4.5, J * s = 3.7, 3.1, H-4 '); 4.90 (dd, 1H, Jgem = 12.2, J ^ = 3.1, H-5'a); 6.13 (dd, 1H, J3'2 '= 6.0, J3'4' = 4,5, H-3 '); 6.19 ’(dd, 1H, J22 = 6.0, J2X = 5.6, H-2 '); 6.80 (d, 1H, JX2 =

5.6, H-1 '); 7.37 (m, 2H, H-m-Bz); 7.40 (s, 1H, H-6); 7.41 (dd, 1H, J5.4 = 5.0, J5.2 = 3.0, H-5-thienyl); 7.41 and 7.50 (2Xm, 2X2H, H-m-Bz); 7.55,7.57 and 7.61 (3 X m, 3 X 1H, H-p-Bz); 7.64 (dd, 1H, J45 = 5.0, J42 = 1.3, H-4- thienyl); 7.95 (dd, 1H, J25 = 3.0, J2 4 = 1.3, H- 2-thienyl); 7.95, 8.01 and 8.14 (3 X m, 3 X 2H, H-o-Bz); 8.89 (s, 1H, H-2) .13CNMR (151MHz, CDCI3): 63.59 (CH2-5 '); 71.39 (CH-3 '); 73.95 (CH-2 '); 80.38 (CH-4 '); 86.05 (CH-1 '); 106.20 (C-5); 113.79 (C-4a); 123.88 (CH-6); 125.23 (CH-5-thienyl); 128.40 (C - / - Bz); 128.50 and 128.54 (CH-m-Bz); 128.66 (C - / - Bz); 128.73 (CH-m-Bz); 129.10 (CH-4-thienyl); 129.30 (C - / - Bz); 129.40 (CH-2-thienyl);

129.69,129.82y129.85 (CH-o-Bz); 133.53,133.74y133.76 (CH-p-Bz); 137.71 (C-3-thienyl); 151.04 (C-7a); 151.94 (CH-2); 154.89 (C-4); 165,10,165.39 and166.14 (CO). MS FAB, m / z (rel.%): 680 (100) [M + H]. HR MS (FAB): calcd for C36H2 and ClN3O / S [M + H] 680,1258, found 680,1247.

Example 33. Effects of the compounds on the distribution of the cell cycle in human T lymphoid cells

[0240] The CCRF-CEM cell line of human T lymphoid cells is treated with the compounds examined for 72 hours with the concentrations corresponding to the CC50 value of each compound. At the end of the incubation, the cells are harvested by centrifugation, washed, and fixed in ethanol. The fixed cells are stained with propidium iodide in a buffer containing RNase A and the cell cycle distribution analysis is performed by flow cytometry using a BD FACSAria instrument. The information is processed using version 4.1 of the FACSDiva software and is presented as a percentage of the cell population analyzed in phase G1, S and G2 / M. The distribution of the cell cycle is determined in parallel for untreated and treated cells and the relative change for each phase of the cell cycle is calculated.

[0241] The results of the representative compounds are summarized in Table 2. The information represents changes in the frequency of each phase of the cell cycle in the treated cells in relation to the untreated control (the relative fraction of each phase of the analyzed cell cycle. in the untreated control it has the value of 1).

[0242] The primary information is shown in Table 3, with values representing the percentage distribution of each phase of the cell cycle in the total cell population.

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Table 2

 Compound

 Structure Relative change in the cell cycle phase compared to untreated control *

 G1

 S G2 / M

 Example 5

 w fT N j V HO OH 0.57 1.38 1.19

 Example 6

 or w US OH 0.52 1.34 1.54

 Example 21

 9 / w HE? 0.74 1.12 1.38

 Example 20

 j-ki qH 0.61 1.06 2.00

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Table 3

 Example 5

 G1% S% G2 / M%

 Control 1

 42.93 44.94 12.14

 Control 2

 45.11 43.26 11.62

 0.3 | jM 1

 26.14 61.98 11.89

 0.3 jM 2

 23.61 59.99 16.41

 Example 6

 G1% S% G2 / M%

 Control 1

 42.93 44.94 12.14

 Control 2

 45.11 43.26 11.62

 0.3 jM 1

 30.82 54.65 14.53

 0.3 jM 2

 14.66 63.29 22.05

 Example 21

 G1% S% G2 / M%

 Control 1

 43.11 41.14 15.74

 Control 2

 43.06 39.19 17.75

 0.3 jM 1

 30.83 46.37 22.80

 0.3 jM 2

 32.73 43.74 23.53

 Example 20

 G1% S% G2 / M%

 Control 1

 42.72 43.77 13.51

 Example 20

 G1% S% G2 / M%

 Control 2

 41.49 44.36 14.15

 1.5 jM 1

 22.32 47.49 30.19

 1.5 jM 2

 28.81 45.95 25.24

[0243] A treatment with each of the compounds examined affects the distribution of the cell cycle in human T lymphoid cells. Representative compounds reduce the fraction of the cells in the G1 phase and correspondingly increase the fraction of cells in the S and G2 / M phases, indicating that the compounds may block the progress of cell proliferation and / or inhibit growth of tumor cells through several phases of the cell cycle.

Example 34. Induction of apoptosis by the compounds of the invention

[0244] The CCRF-CEM cell line of human T lymphoids is treated with the compounds examined for 72 hours with some concentrations based on the CC50 value of each compound. At the end of the incubation, the cells are cultured by centrifugation, washed and resuspended in a buffer containing calcium supplemented with a conjugate of annexin V-FITC and propidium iodide (PI-propidium iodide). After the end of the incubation, the cells are washed again and analyzed immediately by flow cytometry using the BD FACSAria instrument. The information is processed using version 7.2.5 of the FlowJo software and is presented as a percentage of the analyzed cell population that is considered healthy (double negative), early apoptotic (positive annexin V, negative PI), late apoptotic / necrotic (double positive) or purely necrotic (positive of PI, negative of annexin V). Untreated cells serve as a negative control that refers to apoptosis that continues naturally in cell culture.

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[0245] The results of the representative compounds are summarized in Table 4, with values representing the percentage distribution of differentially stained sub-populations as mentioned above.

Table 4

 Cellular distribution (%)

 Concentration (microM) Healthy Early apoptotic Late apoptotic / necrotic Necrotic

 Untreated control

   89 4 4 3

 0.2 40 14 40 6

 0.2 60 8 28 4

 0.4 33 11 49 7

[0246] Treatment with each of the compounds examined results in the induction of apoptosis in human T lymphoid cells. This effect depends on the concentration.

Example 35. The following illustration represents pharmaceutical dosage forms, containing a compound of the formula I ('Compound X'), for therapeutic and prophylactic uses in humans.

[0247]

 (i) Tablet 1

 mg / tablet

 Compound X =

 100.0

 Lactose

 77.5

 Povidone

 15.0

 Croscarmellose sodium

 12.0

 Microcrystalline cellulose

 92.5

 Magnesium stearate

 3.0 300.0

 (ii) Tablet 2

 mg / tablet

 Compound X =

 20.0

 Microcrystalline cellulose

 410.0

 Starch

 50.0

 Sodium Starch Glycolate

 15.0

 Magnesium stearate

 5.0

 500.0

(iii) mg capsule / capsule

 Compound X =

 10.0

 Colloidal Silicone Dioxide

 1.5

 Lactose

 465.5

 Previously gelatinized starch

 120.0

 Magnesium stearate

 3.0

 600.0

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(iv) Injection 1 (1 mg / milliliter) mg / milliliter

 Compound X = (free acid form)

 1.0

 Sodium dibasic phosphate

 12.0

 Monobasic sodium phosphate

 0.7

 1.0 N sodium chloride of a sodium hydroxide solution

 4,5

 (PH adjustment to 7.0-7.5)

 q.s.

 Water for injection

 q.s. 1 ml

(v) Injection 2 (10 mg / milliliter) mg / milliliter

 Compound X = (free acid form)

 10.0

 Monobasic sodium phosphate

 0.3

 Sodium dibasic phosphate

 1.1

 Polyethylene glycol 400 01 N of a sodium hydroxide solution

 200.0

 (PH adjustment to 7.0-7.5)

 q.s.

 Water for injection

 q.s. 1 ml

 (v) Spray

 mg / can

 Compound X =

 20.0

 Oleic acid

 10.0

 Trichloromonofluoromethane

 5,000.0

 Dichlorodifluoromethane

 10,000.0

 Dichlorotetrafluoroethane

 5,000.0

[0248] The aforementioned formulations can be obtained by conventional procedures known in the pharmaceutical industry.

[0249] The invention was described in reference to various specific and preferred implementations and techniques. However, it should be clear that many variations and modifications can be made while remaining within the scope of the invention.

Claims (13)

5 10 fifteen twenty 25 30 35 40 Four. Five fifty 55 60 65 Claims 1. A compound of formula I: image 1 Where: R1 is a (Ci-C6) alkyl, a hydroxy (Ci-C6) alkyl, an aryl, an aryl (Ci-C6) alkyl, a heteroaryl selected from furanyl, thienyl, pyrrolyl, thiazoyl, imidazolyl, pyridyl, selenophenyl, or pyrazolyl, or heteroaryl (Ci-C6) alkyl, where each aryl or heteroaryl is optionally substituted with one or more groups selected from (Ci-C6) alkyl, (Ci-C6) alkoxy, (Ci-C6) alkylthio, halo, amino nitro cyano trifluoromethyl, or hydroxy; Y R2 is a hydrogen, a heteroaryl, a halo or an aryl that is optionally substituted with one or more groups selected from (Ci-C6) alkyl, (Ci-C6) alkoxy, (Ci-C6) alkylthio, halo, amino, nitro cyano trifluoromethyl, or hydroxy; or one of its salts; As long as every time Ri is an unsubstituted phenyl, then R2 is not hydrogen. 2. The compound of claim i, wherein Ri is a heteroaryl. 3. The compound of claim i, wherein Ri is a furanyl, a thienyl, a pyrrolyl, a thiazoyl, an imidazolyl, a pyridyl, a selenophenyl, or a pyrazolyl. 4. The compound of claim i, wherein Ri is a 5-membered heteroaryl, or a hydroxy- (C-C4) alkyl, R2 is a hydrogen or a halo; or one of its salts. 5. The compound of claim i, wherein Ri is a furanyl, a thienyl, a pyrrolyl, a thiazoyl, an imidazolyl, a pyridyl, a selenophenyl, or a pyrazolyl, R2 is hydrogen or halo, or one of its salts. 6. The compound of claim 5, wherein R2 is hydrogen. 7. The compound of claim 5, wherein R2 is halo. 8. A compound of any of claims i to 7 for use to inhibit tumor / cancengene growth in a subject. 9. A compound of any one of claims 1 to 7 for use to inhibit cell proliferation in tumor / cancer cells in a subject. 10. A compound of any one of claims 1 to 7 for use to treat a cell proliferation disease in a subject. 11. A compound of any one of claims 1 to 7 for use in treating a neoplasic disease in a subject. 12. A compound of any one of claims 1 to 7 for use in the treatment of a tumor or cancer in a subject. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and one or more pharmaceutically acceptable carriers.